expression and function of the endocannabinoid …...expression and function of the endocannabinoid...

Review ArticleExpression and Function of the Endocannabinoid System inthe Retina and the Visual Brain

Jean-Franccedilois Bouchard1 Christian Casanova2

Bruno Ceacutecyre12 and William John Redmond12

1Laboratoire de Neuropharmacologie Ecole drsquooptometrie Universite de Montreal CP 6128 Succursale Centre-VilleMontreal QC Canada H3C 3J72Laboratoire des Neurosciences de la Vision Ecole drsquooptometrie Universite de Montreal CP 6128 Succursale Centre-VilleMontreal QC Canada H3C 3J7

Correspondence should be addressed to Jean-Francois Bouchard jean-francoisbouchardumontrealca

Received 22 July 2015 Revised 24 September 2015 Accepted 27 September 2015

Academic Editor Preston E Garraghty

Copyright copy 2016 Jean-Francois Bouchard et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system Cannabinoidreceptors are seven transmembrane G-protein coupled receptors favoring Gio proteinThey are known to play an important role invarious processes including metabolic regulation craving pain anxiety and immune function In the last decade there has been agrowing interest for endocannabinoids in the retina and their role in visual processingThe purpose of this review is to characterizethe expression and physiological functions of the endocannabinoid system in the visual system from the retina to the primaryvisual cortex with a main interest regarding the retina which is the best-described area in this system so far It will show that theendocannabinoid system is widely present in the retina mostly in the through pathway where it can modulate neurotransmitterrelease and ion channel activity although some evidence also indicates possible mechanisms via amacrine horizontal and Mullercells The presence of multiple endocannabinoid ligands synthesizing and catabolizing enzymes and receptors highlights variouspharmacological targets for novel therapeutic application to retinal diseases

1 Introduction

The endocannabinoid (eCB) system is a complex neuromod-ulatory system consisting of two classical receptors cannabi-noid receptor type 1 (CB1R) and cannabinoid receptor type 2(CB2R) their endogenous ligands named endocannabinoidsand enzymes responsible for their synthesis and degradationThis system can modulate both inhibitory and excitatorysynapses in a short- or long-lasting manner They mostly actthrough a retrograde mechanism in which the postsynapticon demand release of eCBs will lead to a presynaptic CB1Ractivation in order to reduce transmitter release [1ndash3] TheseeCBs the two best defined of which are N-arachidonoylethanolamide also known as anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are then quickly degradedmostly via fatty acid amide hydrolase (FAAH) activity forAEA and monoacylglycerol lipase (MAGL) for 2-AG Thisretrograde release can also act on CB2R in large part situated

on glial cells in the adult nervous system [2 4] CB1Rand CB2R are both 7-transmembrane G-protein coupledreceptors with a strong preference toward Gio coupling[5 6] although Gq [7] and Gs [8] coupling has also beenreported for CB1R in the past This can lead among othersto a reduction of presynaptic glutamate and GABA releaseCannabinoids could also have neuroprotective and plasticity-mediating properties For general reviews on the eCB signal-ing system see [2 9ndash11]

In recent years the role of eCBs in visual function hasbeen intensely studied Recent reports suggest that the eCBsystem could play an instrumental role at all levels of thevisual system The vast majority of these studies focused onthe effects of eCBs on adult retinal functions and only a fewinvestigated the effects of cannabinoids on visual perception

Reports showed that Δ9-tetrahydrocannabinol (THC)increased the recovery time from bright foveal glare byseveral seconds [12] Acute effects on vision from smoking

Hindawi Publishing CorporationNeural PlasticityVolume 2016 Article ID 9247057 14 pageshttpdxdoiorg10115520169247057

2 Neural Plasticity

marijuana include a reduction in Vernier and Snellen acu-ity alterations in color discrimination and an increase inphotosensitivity [13 14] Some anecdotal reports also showedthat Jamaican fishermen smoke marijuana to improve dimlight vision when fishing at night [15] These results havebeen corroborated by another study that measured moreprecisely the night vision of Moroccan fishermen usingcannabis to improve visual perception [16]The authors notedincreased night vision following THC or cannabis ingestionand suggested that these effects were produced locally inthe retinaThese intriguing findings have certainly fascinatedvarious researchers who then began to study the expression ofthe eCB system in the visual system with a focus on the adultretinaWhile still scarce there are now increasing evidence oftransient receptor and enzymatic machinery expression dur-ing development Section 2 and Section 3 of this review willdescribe the expression (Section 2) and function (Section 3)of eCBs in the adult retina whilst Section 4will focus on theseduring development (Section 4)

2 Cannabinoid Expression inthe Visual System

21 Ocular Tissues It is well established that marijuana con-sumption induces vasodilatation in conjunctiva noticeableby a reddish color change in the eyes and a reduction inintraocular pressure [12] It was first believed that marijuanaexerted its effects systemically through the central nervoussystem (CNS) However it became evident that cannabinoidscan act locally on cannabinoid receptors present in variouscell types in the eye [17] Physiological and biochemicalstudies demonstrated the presence of the eCB system invarious regions of ocular tissues The CB1R mRNA is foundin the ciliary body of rat bovine and human as well as inthe trabecular meshwork in bovine and human [18ndash21] CB1Ris also detected in the nonpigmented ciliary epithelium inhuman and bovine tissues and conjunctival epithelium inmouse and human [19 22]The bovine corneal epithelial cellsexpress among others CB1R MAGL 120572120573 hydrolase domain6 (ABHD6) 120572120573 hydrolase domain 12 (ABHD12) and N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD)mRNA [23] Furthermore AEA and 2-AG as well as otherN-acyl ethanolamides such as palmitoylethanolamide (PEA)are present in human ocular tissues except for the lens [2024]

22 Adult Retina

221 Endocannabinoids The two major eCBs (AEA and 2-AG) are present in the retina of adult rodents [17] bovines[25] and humans [20] Most of the studies comparing AEAto 2-AG expression in the retina concluded that 2-AG levelsare significantly higher than AEA thus human and bovineretinas contain 25 times more 2-AG compared to AEA[20 25 26] PEA was detected in the rat and human andoleoylethanolamide (OEA) another endocannabinoid-likeN-acyl ethanolamide was also measured in the rat retina[17] In human 2-AG is mostly produced in the retina while

Table 1 Endocannabinoid levels in the adult retina of variousspecies

Endocannabinoids Concentration(pmolg) Species

2-arachidonoyl glycerol(2-AG)

297013931600

Rat [17]Human [20]Bovine [25]

Anandamide (AEA)

Under detection level200003664

Rat [17]Rat [26]

Human [20]Bovine [25]

Palmitoylethanolamide(PEA)

130200

Rat [17]Human [20]

Oleoylethanolamide (OEA) 55 Rat [17]

AEA and PEA are mainly expressed in the iris [20] Theendocannabinoid levels in the retina are presented in Table 1

The content of eCBs varies in certain disease statessuggesting the importance of eCBs in maintaining ocularhomeostasis For instance 2-AG levels decrease in the ciliarybody of patients with glaucoma [20] but increase in the irisof patients with diabetic retinopathy [24] Similarly PEAlevels are lower in the ciliary body and the choroid ofglaucomatous human retinas [20] but higher in the ciliarybody of diabetic retinopathy human retinas [24] Patientswith age-related macular degeneration (AMD) and diabeticretinopathy also showed widespread increases of AEA levelsin the retina choroid ciliary body and cornea [24] It isbelieved that the upregulation of eCBs in these disorders maycontribute to cell protection in part by the anti-inflammatoryand neuroprotective properties of eCBs [24]

222 Cannabinoid Receptors CB1R was extensively studiedin the retina of various species using techniques such asin situ hybridization reverse transcription polymerase chainreaction (RT-PCR) Western blot or immunohistochemistryCB1R was first localized in the ganglion cell layer (GCL) andinner nuclear layer (INL) of the rat retina [27] Since thenCB1R expression was detected in the retinas of human mon-keymouse rat chick salamander and goldfishwith a similarlabeling in the outer plexiform layer (OPL) inner plexiformlayer (IPL) and GCL [17 22] A schematic illustration of themouse retina organization is presented in Figure 1 Retinalprotein distribution of CB1R is presented in Table 2 and itsexpression for different species is illustrated in Figure 2

The cannabinoid receptor type 2 (CB2R) distribution inthe retina has been less extensively studied than CB1R Thiscould be explained in part by the lack of specific markers forCB2R [28ndash30] and by initial reports revealing an expressionpattern restricted to immune cells It was first believed thatCB2R was not expressed in the embryonic and adult ratretina [18 27] Then CB2R mRNA localization was shownin photoreceptors INL and GCL of the rat retina [31]More recently protein expression of CB2R was detected inretinal pigment epithelium (RPE) inner segments of thephotoreceptors and horizontal and amacrine cells of the ratretina [32] Furthermore a recent report localized CB2R in

Neural Plasticity 3

GCL

IPL

INL

OPL

ONL

OSIS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Figure 1 Schematic illustration representing the organization of the mouse retina Rod (R) and cone (blueC) photoreceptors have their cellbodies in the outer nuclear layer (ONL) and extend inner (IS) and outer (OS) segments Photoreceptors axons synapse in the outer plexiformlayer (OPL) with horizontal (yellowH) and bipolar (magentaRBC-CBC) cellsThe inner nuclear layer (INL) also contains amacrine (redA)and Muller cells (M) Bipolar cells synapse to amacrine and ganglion (blueG) cells in the inner plexiform layer (IPL) Ganglion cell axonsform the optic nerve in the ganglion cell layer (GCL) and carry signals to the brain

Table 2 Cannabinoid receptor type 1 protein distribution in theadult retina of various species

Retinal cells

Photoreceptors

Expression in the inner [17 56] and outersegments [22]Strong labeling in the cone pedicles[17 51 53 56 78]

Horizontal cells Expression in the membrane but not indendrites [17 51 56]

Bipolar cells Expression in the dendrites cell body andaxons of rod bipolar cells [17 51]

Amacrine cells Expression in amacrine cells includingGABAergic amacrine cells [17 51 56 65]

Inner plexiformlayer

Unspecified expression in the IPL [17 22 53]Expression in the synapses of rod bipolar cells[51]Higher expression in the synapses of ON conebipolar cells compared to OFF cone bipolarcells [78]

Ganglion cells Expression in the cell body and fibers[17 22 53 56 83]

Muller cells Absence of expression [17 53 56]Expression in the goldfish retina only [78]

cone and rod photoreceptors horizontal cells some amacrinecells and bipolar and ganglion cells of the mouse retina[33] CB2R is also expressed in the vervet monkey retinabut exclusively in Muller cells [34] Finally CB2R mRNAexpression was also recently found in the goldfish retina

Table 3 Cannabinoid receptor type 2 protein distribution in theadult retina

Retinal cells

Photoreceptors

Expression in the outer and inner segments ofcones [33]Absence of expression in cone pedicles [33]Expression in the inner and outer segmentsand cell body of rods [33]

Horizontal cells Expression at the membrane of the soma andin horizontal cells dendrites [32 33]

Bipolar cells

Expression in the membrane of the soma andaxons of rod bipolar cells [33]Expression in the membrane of the soma ofcone bipolar cells [33]

Amacrine cells Expression in some subtypes [32 33]Ganglion cells Expression in the soma [32 33]

Muller cells

Absence of expression at the membrane of thesoma in Muller cells inner and outer processes[33]Expression in Muller cellsrsquo processes in thevervet monkey only [34]

however its precise distribution is still unknown [35] Retinalprotein distribution of CB2R is presented in Table 3 and itsexpression for different species is illustrated in Figure 3

223 Cannabinoid-Like Receptors In recent years the G-protein coupled receptor 55 (GPR55) was suggested to actas a cannabinoid receptor since it interacts with AEA and

4 Neural Plasticity

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Human Mouse

Primate Rat

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Figure 2 Schematic illustration representing the distribution ofCB1R in the adult retina of several species CB1R expressionwas demonstratedin dark gray retinal cells while CB1R presence was noted in light gray retinal layers without precise localization OS outer segments ofphotoreceptors IS inner segments of photoreceptors ONL outer nuclear layer OPL outer plexiform layer INL inner nuclear layer IPLinner plexiform layer GCL ganglion cell layer C cones R rods H horizontal cells CBC cone bipolar cells RBC rod bipolar cells Aamacrine cells G ganglion cells M Muller cells

THC [36] Due to the lack of specificity of GPR55 markersonly one report studied its expression in the retina In thevervet monkey retina GPR55 is present exclusively in rodswith most prominent staining in their inner segments [37]

Another cannabinoid-like receptor present in the retinais the transient receptor potential vanilloid 1 (TRPV1) whichbinds eCBs such as AEA andN-arachidonoyl dopamine [38]It was first localized in photoreceptor synaptic ribbons and inamacrine cells of goldfish and zebrafish retinas [39 40] In therat retina TRPV1 was found inmicroglial cells blood vessels

and astrocytes and in neuronal structures such as synapticboutons of both plexiform layers as well as in cell bodies ofthe INL and GCL [41] TRPV1 mRNA was also detected inganglion and Muller cells in the rat retina [42] In the rabbitand human retina TRPV1 is intensely expressed in the RPE[43] TRPV1 is also present in the outer nuclear layer (ONL)and INL and at the end of the nerve fiber layer as well as inMuller cells of the rabbit retina [43]

TheG-protein coupled receptor 18 (GPR18) is activated byN-arachidonoyl glycine (NAGly) the endogenousmetabolite

Neural Plasticity 5

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Mouse Primate

Rat

Figure 3 Schematic illustration showing the expression of CB2R in the adult retina of several species CB1R expression was demonstratedin dark gray retinal cells while CB2R presence was noted in light gray retinal layers without precise localization OS outer segments ofphotoreceptors IS inner segments of photoreceptors ONL outer nuclear layer OPL outer plexiform layer INL inner nuclear layer IPLinner plexiform layer GCL ganglion cell layer C cones R rods H horizontal cells CBC cone bipolar cells RBC rod bipolar cells Aamacrine cells G ganglion cells M Muller cells Scale bar 20 120583m

of AEA and is suggested to be the ldquoabnormal-CBDrdquo (Abn-CBD) receptor [44] Only one study examined the expressionof GPR18 in the retina It is mostly expressed in the IPL andOPL and in the endothelium of retinal vessels in the rat [45]

Furthermore there is growing evidence that the intracel-lular peroxisome proliferator-activated receptors (PPARs) arethe targets of cannabinoid ligands PPARs belong to a familyof nuclear receptors comprising three isoforms 120572 120575 and 120574(see [46] for review) PPAR 120572 120575 and 120574 are diffusely expressed

in the retina and the RPE of humans and mice [47] PPARsare expressed in cultures of primary RPE cells and ARPE-19cells (a human RPE cell line) [48] PPAR1205741 and PPAR120575 aremoderately expressed in both cell types while PPAR120572 is onlyexpressed in ARPE-19 cells PPAR120572 and 120575 are also expressedin freshly isolated RPE but PPAR120574 is absent [48]

224 Synthesizing and Catabolic Enzymes The first retinallocalization of the enzymes responsible for 2-AG synthesis

6 Neural Plasticity

was recently reportedDiacylglycerol lipase alpha (DAGL120572) ispresent in the two synaptic layers of themouse retina namelythe OPL and the IPL [49] Indeed DAGL120572 is localized inpostsynaptic terminals of type 1 OFF cone bipolar cells aswell as in the dendrites of unidentified bipolar cells DAGL120572expression was recently found in the rat retina as its presencewas detected in cone and rod photoreceptors horizontalcellsrsquo processes some cone bipolar cells axonal connectionsamacrine cells and ganglion cells [50] DAGL120573 is exclusivelyexpressed in retinal blood vessels [49]

The hydrolyzing enzyme FAAH which is responsible forthe degradation of AEA is localized in the retina of mice[49] rats [51 52] and primates [53] It was first detectedin horizontal cells dopamine amacrine cells dendrites ofstarburst amacrine cells and large ganglion cells of the ratretina [51] Further studies revealed the expression of FAAHin cone photoreceptors rod bipolar cells and some ganglioncells in the rat retina as well as in the inner segmentsof photoreceptors ONL and GCL in a subpopulation ofamacrine and cone bipolar cells and in the axon terminalsof rod photoreceptors [49 52] In the vervet monkey retinaFAAH is localized in cones cone pedicles rod spherules coneand rod bipolar cells and ganglion cells [53]

The metabolizing enzyme MAGL is expressed in themouse and rat retina It was first detected in the OPL IPLand GCL [49] In the IPL MAGL is particularly present intwo laminae one in the central IPL and the other in the distalIPL In the OPL MAGL is found in rod spherules and conepedicles A recent study revealed that in the rat retinaMAGLis expressed in amacrine and Muller cells as well as in theaxonal connections of type 2 cone bipolar cells [50]

The expression of the metabolizing ABHD6 a serinehydrolase [54 55] was reported in the mouse retina It islocalized in GABAergic amacrine cells and ganglion cellsand in the dendrites of ganglion cells or displaced amacrinecells [49] As for the synthesizing enzyme NAPE-PLD amajor synthesizing enzyme of AEA and OEA from lipids itis expressed in the rat retina [56]

For now no studies have revealed the presence ofABHD12 in the retina [55] as the study of ABHD12 requiresthe development of a specific antibody against this protein

23 Cannabinoid System Expression in the Primary VisualCortex As CB1R is the most abundant GPCR in the CNS itis not surprising that the eCB system is also present in severalvisual brain regions beyond the retina For instance CB1Ris expressed throughout the dorsal lateral geniculate nucleus(dLGN) of vervet monkeys with a prominent labeling inthe magnocellular layers [57] The catabolic enzyme FAAHshows the same pattern of expression while the synthesizingenzyme NAPE-PLD is expressed homogenously throughoutthe dLGN [57] All CB1R FAAH and NAPE-PLD are weaklyexpressed in the koniocellular layers Furthermore CB1Ris expressed in the primary visual cortex (V1) of macaquemonkeys with the highest density observed in layers V-VIand the absence of labeling in layer IV [58] CB1R is intenselyexpressed in layers IIIII and VI of the striate cortex of theadult mouse [59] where it is mainly localized at vesicu-lar GABA transporter-positive inhibitory nerve terminals

The eCB system also appears to be of importance in devel-opment as CB1R protein expression increased throughoutthe development of V1 with a specific laminar pattern ofCB1R appearing at postnatal day 20 (P20) and remaining untiladulthood [59]

3 Cannabinoid Function in the Visual System

31 Retina In the retina cannabinoids inhibit the release ofvarious neurotransmitters Indeed CB1R agonists decreasethe release of [3H]-noradrenaline and [3H]-dopamine in theguinea pig [60] via a Gio-dependent mechanism [61 62]In general though the cannabinoid-mediated system in thevertebrate retina appears to act mainly via the ldquothroughrdquopathway as cannabinoid receptors are concentrated in pho-toreceptors and bipolar and ganglion cells that is cells usingglutamate as a principal neurotransmitter [63] Afirst proof ofconcept for the importance of CB1R-mediated modulation ofglutamate release came from the inhibition by cannabinoidsof [3H]-D-aspartate (a substitute of L-glutamate for high-affinity uptake sites) release following ischemia or K+ channelactivation in isolated bovine retina [64] Some evidence alsosuggests a regulatory effect on GABAA receptor-mediatedinward currents from WIN55212-2 a synthetic cannabinoidwith similar affinity to both CB1R and CB2R on low sponta-neous transmission in embryonic chick amacrine cells [65]It is important to note that in this study Warrier andWilsonused a high concentration of WIN55212-2 which couldproduce off-target effects At this concentration the effectof WIN55212-2 was not blocked by SR141716A a selectiveCB1R inverse agonist Due to the nature ofWIN55212-2 thiseffect could bemediated by CB2R via the activation of a TRP-family type of receptor or via other off-target mechanismsTaken together these various effects may suggest a possiblecannabinoid-mediated tone in transmitter release Yet inin vivo electrophysiological studies only CB2R not CB1Rappears to cause changes to light responses in the mouseretina in vivo recording of electroretinogram responses indi-cates that cnr2-KO animals exhibit increased a-wave ampli-tude under scotopic conditions and different light adaptationpattern in photopic conditions [33] As this review aims atdescribing the anatomical distribution of cannabinoids in theretinamodulatory effects of cannabinoids will be reported bycell type

311 Epithelial Cells In recent years epithelial cells havebeen shown to be of importance in several models of pathol-ogy induced in cultured RPE cells In one study high glucose-mediated apoptosis in ARPE-19 RPE cells was reduced by theoverexpression of FAAH via CB1R blockade and via CB1RsiRNA transfection demonstrating a therapeutic potentialfor FAAH modulation in diabetic retinopathy [66] Anoverexpression of CB1R and CB2R and downregulation ofFAAH were also observed in response to oxidative stressin a model of AMD [67] In a first study cannabinoidagonists were shown to cause neuroprotection in these cellsalthough the specificity of these effects via CB1R or CB2Rmechanism could not be made due to a lack of proper use

Neural Plasticity 7

of inhibitors or specific blockade of the receptors Howeverin a follow-up study by the same authors blockade of theoverexpressed CB1R in this model via specific siRNA con-veyed a neuroprotective effect by causing a downregulation ofoxidative stress signaling and facilitating phosphatidylinosi-tol 31015840-kinase (PI3KAKT) activation a fundamental signalingpathway for cellular apoptosis [68] As the list of eCBskeeps expanding so does the list of their potential targetsFor example the atypical endothelial cannabinoid receptorCBe (for review see [69]) has recently shown promisesas a possible inhibitor of vasoconstriction in the retinalmicrovasculature an autoregulated CNS bed Abn-CBD anagonist of the atypical endothelial cannabinoid receptorcauses an inhibition of the retinal arteriole vasoconstrictioninduced by endothelin-1 This mechanism was independentof CB1RCB2R as well as of GPR55 a receptor for whichAbn-CBD is an agonist N-arachidonoyl glycine a putativeGPR18 agonist showed nearly identical effects as those ofAbn-CBD Bothmechanisms took place via calcium-sensitivepotassium channels (SKCa)The presence of the endotheliumis important for bothmechanisms as these effectswere highlyreduced in its absence [45] Abn-CBD via GPR18 also causedvasodilation of isolated perfused retinal arterioles but onlyon precontracted vessels hinting at a mechanism dependenton vascular tone Intra- and extraluminal administration gavevery different responses and again the presence of epithelialcells was shown to be primordial in this mechanism [70 71]Various cannabinoids could activate PPAR120572 [72] althoughno studies have so far shown an effect of cannabinoids viaPPAR120572 on the visual system Interestingly a recent study byChen et al has demonstrated that fenofibrate a direct agonistof PPAR120572 has a therapeutic potential for the treatment ofdiabetic retinopathy in models of type 1 diabetes [73] Itwould be interesting to investigate if some of the effects ofcannabinoids in this pathology could come from a similarmechanism

312 Photoreceptors Different effects on rod and cone pho-toreceptors have been reported for the salamander and gold-fish following WIN55212-2 addition with a potential bipha-sic response based on concentration for the goldfish Delayedrectifier currents (119868K) were suppressed by WIN55212-2 incones and rods whereas Ca2+ currents (119868Ca) were enhancedin rods and suppressed in cones [74 75] which couldpotentially be translated to an increased transmitter releasethus reducing light sensitivity A cannabinoid-mediated ret-rograde suppression of membrane currents via 2-AG releaseon goldfish cones in retinal slices was also tested by Fanand Yazulla [76] These authors found the existence of aretrograde transmission in cones with bipolar cell dendritesas the likely source of 2-AG Furthermore the retrogradesuppression of 119868K is mediated by Ca2+ dependent release of 2-AG from bipolar cell dendrites Cannabinoids also preservedcone and rod structure as well as function and synapticconnectivity with postsynaptic neurons in a transgenicmodelfor autosomal dominant retinitis pigmentosa Indeed HU-210 a more potent and longer lasting synthetic analogue ofTHC increased the scotopic a- and b-wave amplitudes intreated animals and preserved photoreceptor degeneration

and synaptic contacts between photoreceptors and bipolar orhorizontal cells [77]

313 Bipolar Cells As for photoreceptors Straiker andYazullarsquos groups were the first to describe a cannabinoid-mediated effect in the salamander and the goldfish respec-tively [17] WIN55212-2 reversely inhibited 119868Ca in the sala-mander [6] On the goldfish large ON-type bipolar cellscannabinoid agonists such as CP54490 (a full agonist at bothCB1R and CB2R) and WIN55212-2 inhibited 119868K and thisinhibition could be reversed by using SR141716A an inverseagonist for CB1R [78] As SR141716A did not cause by itselfmuch increase in 119868K of someON bipolar cells and no increaseon others an eCB modulating tone present in this arearemains unclear This lack of direct modulation of bipolarcells by cannabinoids does not necessarily translate into nocannabinoid-mediatedmechanism for these cells Retrogradesignaling from ganglion cells is still a plausible mechanismand was first demonstrated for 2-AG [76]

WIN55212-2 also inhibits the enhancement in 119868K seenfollowing the activation of D1 receptors It has thus beenproposed that the cannabinoid and dopaminergic systemhave opposite properties on bipolar cells SR141716A anda pretreatment with pertussis toxin could both block thismechanism althoughWIN55212-2 by itself did not cause anincrease in conductivity on 119868K [78] Cannabinoids effects onON bipolar cells have thus been associated with a tonic effectwhereas D1-mediated effects have been described as phasic[63]

314 Amacrine Cells The neuroprotective effects of endoge-nous and synthetic cannabinoids on the viability of amacrinecells were studied using an in vivo AMPA excitotoxicitymodel of retinal neurodegeneration AEA HU-210 andmethanandamide (a stable synthetic chiral analogue of AEA)afforded partial recovery following the AMPA-induced exci-totoxicity of both bNOS-positive and cholinergic amacrinecells [79] This neuroprotection is mediated by a mechanisminvolving CB1R PI3KAkt andor MEKERK12 signalingpathways but not CB2R

315 Retinal Ganglion Cells It has been reported thatWIN55212-2 AEA the selective CB1R agonist arachidonoyl-2-chloroethylamide (ACEA) and the CB2R agonist CB65inhibit 119868K via the tetraethylammonium (TEA)-sensitiveK(+) current component in rat RGCs These effects couldnot be reversed either by the CB1R inverse agonistsAM251SR141716A or by the CB2R inverse agonist AM630[80] although both CB1Rs andCB2Rs are present on ganglioncells The authors suggest that eCBs modulate potassiumchannels in rat RGCs in a receptor-independent manner asdemonstrated in other cells [81 82] An earlier in vitro studyshowed a partial inhibition of high-voltage activated Ca2+channels with WIN55212-2 that could be reversed by bothSR141716A and AM281 in cultured rat RGCs [83] A recentstudy showed that the agonist WIN55212-2 caused a signif-icant reversible reduction in the frequency of spontaneouspostsynaptic currents (SPSCs) in RGCs of adult and young

8 Neural Plasticity

mice [84] This effect was caused by presynaptic bindingto cannabinoid receptors as it did not alter the kinetics ofSPSCs The authors also found that the release probabilityof GABA and glutamate was significantly reduced by theagonist As the largest reduction of the frequency of bothGABAergic and glutamatergic SPSCs was observed in youngmice this suggests that the eCB system might play a role inthe developmental maturation of synaptic circuits

In addition to their effect at the level of ionic channelseCBs via CB1R have neuroprotective properties In factblockade of FAAHproduces neuroprotective effects on RGCsin a rat model of optic nerve axotomy through a CB1R-mediated mechanism which was gradually lost in aginganimals [85] Neuroprotective properties on RGCs were alsoreported with the administration of WIN55212-2 in a ratmodel of acute rise of intraocular pressure induced ischemia[86] Pinar-Sueiro et al proposed that the neuroprotectiveeffect ofWIN55212-2 wasmediated by an inhibition of gluta-matergic excitotoxicity TNF-120572 release and iNOS expressionBut it is not confirmed experimentally Thus cannabinoidagonists such as WIN55212-2 could be relevant targets toprevent degeneration of RGC cells for intraocular pressureinduced ischemia [85] Overall these neuroprotective effectsby cannabinoid-mediated mechanisms are in accordancewith a previous study reporting an increase in FAAH activityand a downregulation of AEA CB1R and TRPV1 follow-ing high intraocular pressure induced ischemia This effectcould be prevented by the administration of the FAAHinhibitor URB597 [26] Furthermore systemic administra-tion of URB597 or intravitreal injection of methanandamidea stable analogue of AEA reduced cell loss in the GCL[26] Furthermore the neuroprotective effects mediated bycannabinoid ligands in the retinamight bemediated byCB2Ras well Indeed CB2R activation results in immunomodula-tion andneuroprotection inmodels of brain injury by alteringinfiltrating macrophages and activated resident microglia[87ndash89] Additional studies are needed to assess the role ofCB2R in retinal neuroprotection Very little is known aboutthe effects of other alternative cannabinoid receptors on RGCfunction Future studies would need to point out if GPR55 orGPR18 activation affects RGCs

Various TRP channels can be activated by tactile andpressure stimuli includingTRPV channels [90ndash93] In RGCsTRPV1 is activated by hydrostatic pressures in isolated ratcells in vitroThis activation causes an increase in intracellularCa2+ and leads to cell apoptosis and could be partially pre-vented by using a nonspecific antagonist iodoresiniferatoxin[42] Ligands acting on the orthosteric site of the receptorsuch as capsaicin could also cause cell death InterestinglyTRPV1 activity on microglia cells in the retina can have aninverse effect and prevent cell apoptosis when hydrostaticpressure is applied [94] It would thus be appealing to verifyif 2-AG AEA and N-arachidonoyl dopamine all agonists ofTRPV1 could act on RGCs via TRPV1 and mediate effectspreviously attributed to classical CBRsMoreover it would beinteresting to validate if both receptors could act in synergyand lead to an increase in intracellular calcium inside thesecells

32 Cannabinoid Function in the Primary Visual Cortex Sofar few studies have looked at the effects of eCBs on centralvisual areas processing CB1R activation alters spontaneousand visual activity in the rat dLGN increasing the sponta-neous bursting and oscillatory activity [95 96] For 28 ofthe geniculate cells the injection of various agonists suchas AEA 2-AG and O2545 a potent water-soluble syntheticcannabinoid increased the visual responses while for theremaining 72 decreased visual discharges were observedThese effects could be blocked by AM251 These studiessuggest that CB1R acts as a dynamic modulator of visualinformation being sent to V1 In layer 23 of V1 eCBs playa crucial role in the maturation of GABAergic release Thedevelopmentalmaturation of GABAergic release between eyeopening and puberty can be affected in dark-reared mice andthis effect can be mimicked by CB1R agonists and blockedby antagonists and was similar in cnr1-KO mice [97 98]GABAergic synapses in layers 23 and 5 have also beenshown to not mature normally in cnr1-KO animals Theseresults suggest that visually stimulated endocannabinoid-mediated long-term depression of GABAergic neurotrans-mission (iLTD) happens in the extragranular layer of themouse visual cortex [99] In another report pharmacologicalblockade of cannabinoid receptors prevents the ocular dom-inance shift in layers IIIII of V1 leaving plasticity intact inlayer IV of juvenile mouse [100] Moreover the applicationof cannabinoid agonists leads to an increase in the ampli-tude and frequency of spontaneous inhibitory postsynapticcurrents and miniature inhibitory postsynaptic currents inmouseV1 [101]The systemic administration of a cannabinoidagonist can also modify the encoding of visual stimuliprimarily by delaying and broadening the temporal responsefunctions of V1 and V2 neurons in macaque monkeys [102]Finally more studies are needed to assess the impact of CB2Rfunction in the primary visual cortex However based on theimpact of CB2R on retinal function it is conceivable thatCB2R could mediate a large variety of effects in the primaryvisual cortex

4 Endocannabinoid Expression andFunction during Retinal Development

As shown in other systems eCBs are well known modulatorsof synaptic transmission and neuronal plasticity mostly viapresynaptic inhibitory mechanisms The impact of the eCBsystem during CNS development has been documented inthe last decade The eCB system regulates the proliferationmigration specification and survival of neural progenitors[103] dictates the differentiation of neurons and controls theestablishment of synaptic connections [104] (for review see[105])The importance of eCBs during neuronal developmentis confirmed by the demonstration that maternal marijuanasmoking or cannabinoid consumption during pregnancycauses cognitive motor and social deficits [106ndash108] (see[109] for review) In addition 2-AG levels in theCNSprogres-sively increase during embryonic development and then peakjust after birth [110 111] However eCB-mediated changes indevelopmental processes are not only limited to the higher

Neural Plasticity 9

brain structures but also can affect the development of theretina

41 Retinal Endocannabinoid Expression CB1R mRNA isexpressed in the rat retina as early as embryonic age 13(E13) which is a good indicator of its possible developmentalimplication [27] By E15 to E17 the GCL expresses CB1RmRNA and from E20-E21 it is present in the GCL as wellas in an unspecified cell layer that appears to be the INL[27] The CB1R is also expressed in the chick retinotectalsystem as soon as E4 with labeling in ganglion cells andthe IPL and INL [112] The CB1R FAAH DAGL120572 andMAGL were also detected during postnatal development ofthe rat retina [50 52 56] The CB1R is present in ganglioncells amacrine cells and horizontal and mitotic cells at P1[56] During retinal development a transient expression ofCB1R was reported in cones and bipolar cells MoreoverFAAH was found at P1 in ganglion and cholinergic amacrinecells and in the course of development it appeared incones horizontal and bipolar cells [52] FAAH is transientlyexpressed in horizontal cholinergic amacrine cells and conebipolar cells suggesting an important redistribution of theenzyme during postnatal retinal development AdditionallyDAGL120572 is expressed early in retinal development as itspresence at P1 is observed in cone and rod photoreceptorshorizontal amacrine and ganglion cells [50] MAGL expres-sion is detected at low levels from P1 to P9 and then itgradually elevated onto adulthood [50] MAGL is constantlyfound in amacrine and Muller cells from P11 onto the adultage Overall the expression of DAGL120572 combined with theabsence of MAGL expression in early postnatal developmentof the retina suggests that 2-AG levels could be elevatedand thus play an active role in retinal development Despitean important body of literature currently available on theinvolvement of eCBs in developmental functions only fewstudies focused on the impact of cannabinoids in retinaldevelopment (see Section 42) It is to be noted that retinasfrom cnr1-KO and cnr2-KO animals do not show obviouschanges in retinal structures as their thickness distributionand morphology were similar to wild-type animals [33] Forthese reasons it is too early to hypothesize on the role of eCBsin retinal development

The TRPV1 receptor is also present in the rat retinafrom E19 onto adulthood [41] From E19 to P5 the TRPV1receptor is detected in the neuroblastic layer in the pigmentepithelium and in a few small cell bodies in the GCL FromP15 onto adulthood TRPV1 is also present in all cell layerswith prominent labeling in the IPL and GCL The precisecellular expression of TRPV1 in the retina is still incompleteSo far TRPV1 has been located in RGC [42] and microglialcells [94]

No studies have yet reported the expression of GPR18 inthe developing retina Ongoing projects from our group haveso far shown that GPR55 mRNA and protein are expressedin the retina of newly born mice more specifically in RGCs[113]

42 Endocannabinoid System Function Only two studiesreported the functional impact of cannabinoids on retinal

development CB1R and CB2R specific agonists induce acollapse of the growth cone of RGC axon and decrease axongrowth [114 115] Conversely the application of CB1R andCB2R specific inverse agonists increases the growth cone sur-face area and the number of filopodia present on the growthcone and increases axon growth The intraocular injectionof CB1R and CB2R specific inverse agonists promotes retinalprojection growth in the dorsal terminal nucleus Moreoverthe importance of GPR55 in neuronal development hasrecently been pointed out by the lipid-signaling of GPR55and one of its ligands lyso-phosphatidyl-120573-D-glucoside inglial-neuron communication in the developing spinal cord[116] GPR55 also modulates the growth rate and the targetsinnervation of retinal projections during development Forinstance the application of GPR55 agonists increases thegrowth cone surface area and the number of filopodia onthe growth cone and also increases the axon growth [113]Furthermore gpr55minusminus mice revealed a decreased branchingin the dorsal terminal nucleus and a lower level of eye-specificsegregation of retinal projections in the superior colliculusand in the dLGN Altogether these studies identify a mech-anism by which the eCB system modulates retinothalamicdevelopment and offer a potential model to explain whycannabinoid agonists affect CNS development

5 Future Directions and Implications

As we have reported in this review CB1R and CB2R are bothpresent in various retinal tissue where they modulate in themost part via retrograde signaling neurotransmitter releaseand where they inhibit potassium and calcium currentsThese effects can thus modulate visual activity as early as theretina level More studies are obviously needed to assess towhat extent a cannabinoid-mediatedmodulation in the retinacould impact visual perception This is especially true giventhat cannabinoid receptors are present in most retinal celltypes As cannabinoids are also present in the visual cortex(including areas beyond V1 and V2) as well as subcorticalregions such as the LGN it may well be that cannabinoidsmodulate visual perception at each level of visual systemhierarchy

The ability of the eCB system to induce various changesin plasticity in central visual areas is now well described(for review see [2]) and some of these plastic changescould potentially be present in the retina Furthermore inthe CNS and as our group and others have previouslydemonstrated in the visual system cannabinoids play animportant role in neuronal development and axon guidanceIt would now be of interest to see if a similar variationin the concentration of receptors enzymatic machineryand endogenous ligands occur during retinal developmentMoreover a better anatomical identification of the variouscannabinoids synthesizing and degrading enzymes noveleCBs and other potential cannabinoid-like receptors such asTRPV1 GPR55 andGPR18 are also needed in order to draw aclearer picture of all the possible targets for various cannabi-noid ligands in the retina and the CNS New methods arealso needed to better localize and find the rapid occurrence ofthe activation of CBRs Finally some mechanisms associated

10 Neural Plasticity

with themodulation of the eCB system in specific areas of theretina have neuroprotective potential and regulate apoptosisand could even potentially help prevent pathologies of theretina such as glaucoma and AMD

6 Conclusion

Endocannabinoids constitute one of the newest neuromod-ulators found in neural and nonneural tissues throughoutthe body Their wide expression in the nervous systemand peripheral organ systems highlights the range of theiractions and their potential in therapeutic applications Strongevidence now suggests a wide distribution of eCBs receptorsand enzymatic machinery in key structures of the visualsystem including a strong presence in the retina Althoughno clear picture can ascertain the specific effects cannabinoidscan have in the retina itself or the visual system as a wholevarious mechanisms in specific cellular structures of theretina have now been reported The cannabinoid systemalso appears to have several roles in neuronal survival andapoptosis in the retina and could be linked with manyother ocular disorders However their specific mechanismsin retinal development neuroplasticity and neuroprotectionneed to be more thoroughly investigated

Conflict of Interests

The authors confirm that there is no conflict of interestsregarding the publication of this paper

References

[1] M Kano T Ohno-Shosaku Y Hashimotodani M Uchi-gashima and M Watanabe ldquoEndocannabinoid-mediated con-trol of synaptic transmissionrdquo Physiological Reviews vol 89 no1 pp 309ndash380 2009

[2] P E Castillo T J Younts A E Chavez and Y HashimotodanildquoEndocannabinoid signaling and synaptic functionrdquo Neuronvol 76 no 1 pp 70ndash81 2012

[3] D Piomelli ldquoThe molecular logic of endocannabinoid sig-nallingrdquoNature ReviewsNeuroscience vol 4 no 11 pp 873ndash8842003

[4] N Stella ldquoEndocannabinoid signaling in microglial cellsrdquoNeuropharmacology vol 56 supplement 1 pp 244ndash253 2009

[5] A C Howlett ldquoInhibition of neuroblastoma adenylate cyclaseby cannabinoid and nantradol compoundsrdquo Life Sciences vol35 no 17 pp 1803ndash1810 1984

[6] A C Howlett and R M Fleming ldquoCannabinoid inhibition ofadenylate cyclase Pharmacology of the response in neuroblas-toma cell membranerdquo Molecular Pharmacology vol 26 no 3pp 532ndash538 1984

[7] J E Lauckner B Hille and K Mackie ldquoThe cannabinoidagonist WIN55212-2 increases intracellular calcium via CB1receptor coupling to Gq11 G proteinsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 102 no 52 pp 19144ndash19149 2005

[8] M Glass and C C Felder ldquoConcurrent stimulation of cannabi-noid CB1 and dopamine D2 receptors augments cAMP accu-mulation in striatal neurons evidence for a G(s) linkage to the

CB1 receptorrdquo The Journal of Neuroscience vol 17 no 14 pp5327ndash5333 1997

[9] K Ahn M K McKinney and B F Cravatt ldquoEnzymatic path-ways that regulate endocannabinoid signaling in the nervoussystemrdquo Chemical Reviews vol 108 no 5 pp 1687ndash1707 2008

[10] V DiMarzo ldquoThe endocannabinoid system its general strategyof action tools for its pharmacological manipulation andpotential therapeutic exploitationrdquo Pharmacological Researchvol 60 no 2 pp 77ndash84 2009

[11] R G Pertwee A C Howlett M E Abood et al ldquoInter-national union of basic and clinical pharmacology LXXIXCannabinoid receptors and their ligands beyondCB1 andCB2rdquoPharmacological Reviews vol 62 no 4 pp 588ndash631 2010

[12] A J Adams B Brown G Haegerstrom-Portnoy M C Flomand R T Jones ldquoMarijuana alcohol and combined drug effectson the time course of glare recoveryrdquo Psychopharmacology vol56 no 1 pp 81ndash86 1978

[13] G F Kiplinger J E Manna B E Rodda et al ldquoDose-responseanalysis of the effects of tetrahydrocannabinol in manrdquo ClinicalPharmacology andTherapeutics vol 12 no 4 pp 650ndash657 1971

[14] W W Dawson C F Jimenez Antillon J M Perez and J AZeskind ldquoMarijuana and visionmdashafter ten yearsrsquo use in CostaRicardquo Investigative Ophthalmology and Visual Science vol 16no 8 pp 689ndash699 1977

[15] M E West ldquoCannabis and night visionrdquo Nature vol 351 no6329 pp 703ndash704 1991

[16] E B Russo A Merzouki J M Mesa K A Frey and P J BachldquoCannabis improves night vision a case study of dark adaptom-etry and scotopic sensitivity in kif smokers of the Rif mountainsof northern Moroccordquo Journal of Ethnopharmacology vol 93no 1 pp 99ndash104 2004

[17] A Straiker N Stella D Piomelli KMackie H J Karten andGMaguire ldquoCannabinoid CB1 receptors and ligands in vertebrateretina localization and function of an endogenous signalingsystemrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 96 no 25 pp 14565ndash14570 1999

[18] A Porcella C Maxia G L Gessa and L Pani ldquoThe humaneye expresses high levels of CB1 cannabinoid receptor mRNAand proteinrdquo European Journal of Neuroscience vol 12 no 3pp 1123ndash1127 2000

[19] W D Stamer S F Golightly Y Hosohata et al ldquoCannabinoidCB1 receptor expression activation and detection of endoge-nous ligand in trabecularmeshwork and ciliary process tissuesrdquoEuropean Journal of Pharmacology vol 431 no 3 pp 277ndash2862001

[20] J Chen I Matias T Dinh et al ldquoFinding of endocannabinoidsin human eye tissues implications for glaucomardquo Biochemicaland Biophysical Research Communications vol 330 no 4 pp1062ndash1067 2005

[21] M D Lograno and M R Romano ldquoCannabinoid agonistsinduce contractile responses throughGio-dependent activationof phospholipase C in the bovine ciliary musclerdquo EuropeanJournal of Pharmacology vol 494 no 1 pp 55ndash62 2004

[22] A J Straiker G Maguire K Mackie and J Lindsey ldquoLocaliza-tion of cannabinoid CB1 receptors in the human anterior eyeand retinardquo Investigative Ophthalmology and Visual Science vol40 no 10 pp 2442ndash2448 1999

[23] N Murataeva S Li O Oehler et al ldquoCannabinoid-inducedchemotaxis in bovine corneal epithelial cellsrdquo InvestigativeOpthalmology amp Visual Science vol 56 no 5 pp 3304ndash33132015

Neural Plasticity 11

[24] I Matias J W Wang A S Moriello A Nieves D F Wood-ward and V Di Marzo ldquoChanges in endocannabinoid andpalmitoylethanolamide levels in eye tissues of patients withdiabetic retinopathy and age-related macular degenerationrdquoProstaglandins Leukotrienes and Essential Fatty Acids vol 75no 6 pp 413ndash418 2006

[25] T Bisogno I Delton-Vandenbroucke A Milone MLagarde and V Di Marzo ldquoBiosynthesis and inactivationof N-arachidonoylethanolamine (anandamide) and N-docosahexaenoylethanolamine in bovine retinardquo Archives ofBiochemistry and Biophysics vol 370 no 2 pp 300ndash307 1999

[26] C Nucci V Gasperi R Tartaglione et al ldquoInvolvement ofthe endocannabinoid system in retinal damage after highintraocular pressure-induced ischemia in ratsrdquo InvestigativeOphthalmology and Visual Science vol 48 no 7 pp 2997ndash30042007

[27] N E Buckley S Hansson G Harta and E Mezey ldquoExpressionof the CB1 and CB2 receptor messenger RNAs during embry-onic development in the ratrdquo Neuroscience vol 82 no 4 pp1131ndash1149 1998

[28] J C Ashton ldquoThe use of knockout mice to test the specificityof antibodies for cannabinoid receptorsrdquoHippocampus vol 22no 3 pp 643ndash644 2012

[29] B Cecyre SThomasM Ptito C Casanova and J-F BouchardldquoEvaluation of the specificity of antibodies raised againstcannabinoid receptor type 2 in the mouse retinardquo Naunyn-Schmiedebergrsquos Archives of Pharmacology vol 387 no 2 pp 175ndash184 2014

[30] BKAtwood andKMacKie ldquoCB2 a cannabinoid receptorwithan identity crisisrdquo British Journal of Pharmacology vol 160 no3 pp 467ndash479 2010

[31] Q Lu A Straiker Q Lu and G Maguire ldquoExpression ofCB2 cannabinoid receptor mRNA in adult rat retinardquo VisualNeuroscience vol 17 no 1 pp 91ndash95 2000

[32] E M Lopez P Tagliaferro E S Onaivi and J J Lopez-CostaldquoDistribution of CB2 cannabinoid receptor in adult rat retinardquoSynapse vol 65 no 5 pp 388ndash392 2011

[33] B Cecyre N Zabouri F Huppe-Gourgues J-F Bouchard andC Casanova ldquoRoles of cannabinoid receptors type 1 and 2 onthe retinal function of adult micerdquo Investigative Ophthalmologyand Visual Science vol 54 no 13 pp 8079ndash8090 2013

[34] J Bouskila P Javadi C Casanova M Ptito and J-F BouchardldquoMuller cells express the cannabinoidCB2 receptor in the vervetmonkey retinardquo Journal of Comparative Neurology vol 521 no11 pp 2399ndash2415 2013

[35] E Cottone V Pomatto F Cerri et al ldquoCannabinoid receptorsare widely expressed in goldfish molecular cloning of a CB2-like receptor and evaluation of CB1 and CB2 mRNA expressionprofiles in different organsrdquo Fish Physiology and Biochemistryvol 39 no 5 pp 1287ndash1296 2013

[36] E Ryberg N Larsson S Sjogren et al ldquoThe orphan receptorGPR55 is a novel cannabinoid receptorrdquo British Journal ofPharmacology vol 152 no 7 pp 1092ndash1101 2007

[37] J Bouskila P Javadi C Casanova M Ptito and J-F BouchardldquoRod photoreceptors express GPR55 in the adult vervetmonkeyretinardquo PLoS ONE vol 8 no 11 Article ID e81080 2013

[38] P M Zygmunt J Petersson D A Andersson et al ldquoVanilloidreceptors on sensory nerves mediate the vasodilator action ofanandamiderdquo Nature vol 400 no 6743 pp 452ndash457 1999

[39] S Zimov and S Yazulla ldquoLocalization of vanilloid receptor 1(TRPV1VR1)-like immunoreactivity in goldfish and zebrafish

retinas restriction to photoreceptor synaptic ribbonsrdquo Journalof Neurocytology vol 33 no 4 pp 441ndash452 2004

[40] S Zimov and S Yazulla ldquoVanilloid receptor 1 (TRPV1VR1)co-localizes with fatty acid amide hydrolase (FAAH) in retinalamacrine cellsrdquo Visual Neuroscience vol 24 no 4 pp 581ndash5912007

[41] M Leonelli D O Martins A H Kihara and L R G BrittoldquoOntogenetic expression of the vanilloid receptors TRPV1 andTRPV2 in the rat retinardquo International Journal of DevelopmentalNeuroscience vol 27 no 7 pp 709ndash718 2009

[42] R M Sappington T Sidorova D J Long and D J CalkinsldquoTRPV1 contribution to retinal ganglion cell apoptosis andincreased intracellular Ca2+ with exposure to hydrostatic pres-surerdquo Investigative Ophthalmology and Visual Science vol 50no 2 pp 717ndash728 2009

[43] M C Martınez-Garcıa T Martınez C Paneda P GallegoA I Jimenez and J Merayo ldquoDifferential expression andlocalization of transient receptor potential vanilloid 1 in rabbitand human eyesrdquo Histology and Histopathology vol 28 no 11pp 1507ndash1516 2013

[44] D McHugh S S J Hu N Rimmerman et al ldquoN-arachidonoylglycine an abundant endogenous lipid potently drives directedcellular migration through GPR18 the putative abnormalcannabidiol receptorrdquo BMC Neuroscience vol 11 article 442010

[45] J MacIntyre A Dong A Straiker et al ldquoCannabinoid andlipid-mediated vasorelaxation in retinal microvasculaturerdquoEuropean Journal of Pharmacology vol 735 pp 105ndash114 2014

[46] S E OrsquoSullivan ldquoCannabinoids go nuclear evidence for acti-vation of peroxisome proliferator-activated receptorsrdquo BritishJournal of Pharmacology vol 152 no 5 pp 576ndash582 2007

[47] A A Herzlich X Ding D Shen R J Ross J Tuo and CChan ldquoPeroxisome proliferator-activated receptor expressioninmurinemodels and humans with age-relatedmacular degen-erationrdquo The Open Biology Journal vol 2 no 1 pp 141ndash1482009

[48] M A Dwyer D Kazmin P Hu D P McDonnell and GMalek ldquoResearch resource nuclear receptor atlas of humanretinal pigment epithelial cells potential relevance to age-related macular degenerationrdquo Molecular Endocrinology vol25 no 2 pp 360ndash372 2011

[49] S S-J Hu A Arnold J M Hutchens et al ldquoArchitecture ofcannabinoid signaling in mouse retinardquo Journal of ComparativeNeurology vol 518 no 18 pp 3848ndash3866 2010

[50] B Cecyre M Monette L Beudjekian C Casanova and J-F Bouchard ldquoLocalization of diacylglycerol lipase alpha andmonoacylglycerol lipase during postnatal development of therat retinardquo Frontiers in Neuroanatomy vol 8 article 150 2014

[51] S Yazulla K M Studholme H H McIntosh and D GDeutsch ldquoImmunocytochemical localization of cannabinoidCB1 receptor and fatty acid amide hydrolase in rat retinardquoJournal of Comparative Neurology vol 415 no 1 pp 80ndash901999

[52] N Zabouri M Ptito C Casanova and J-F Bouchard ldquoFattyacid amide hydrolase expression during retinal postnatal devel-opment in ratsrdquo Neuroscience vol 195 pp 145ndash165 2011

[53] J BouskilaMW Burke N Zabouri C CasanovaM Ptito andJ-F Bouchard ldquoExpression and localization of the cannabinoidreceptor type 1 and the enzyme fatty acid amide hydrolase inthe retina of vervet monkeysrdquo Neuroscience vol 202 pp 117ndash130 2012


[54] W R Marrs J L Blankman E A Horne et al ldquoThe serinehydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptorsrdquo Nature Neuroscience vol 13 no8 pp 951ndash957 2010

[55] J L Blankman G M Simon and B F Cravatt ldquoA comprehen-sive profile of brain enzymes that hydrolyze the endocannabi-noid 2-arachidonoylglycerolrdquoChemistry andBiology vol 14 no12 pp 1347ndash1356 2007

[56] N Zabouri J-F Bouchard and C Casanova ldquoCannabinoidreceptor type 1 expression during postnatal development of therat retinardquo Journal of Comparative Neurology vol 519 no 7 pp1258ndash1280 2011

[57] P Javadi J Bouskila J-F Bouchard and M Ptito ldquoTheendocannabinoid system within the dorsal lateral geniculatenucleus of the vervet monkeyrdquo Neuroscience vol 288 pp 135ndash144 2015

[58] S M Eggan and D A Lewis ldquoImmunocytochemical distribu-tion of the cannabinoid CB1 receptor in the primate neocortexa regional and laminar analysisrdquo Cerebral Cortex vol 17 no 1pp 175ndash191 2007

[59] T Yoneda K Kameyama K Esumi Y Daimyo M Watanabeand Y Hata ldquoDevelopmental and visual input-dependent reg-ulation of the CB1 cannabinoid receptor in the mouse visualcortexrdquo PLoS ONE vol 8 no 1 Article ID e53082 2013

[60] E Schlicker J Timm and M Gothert ldquoCannabinoid receptor-mediated inhibition of dopamine release in the retinardquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 354 no 6 pp 791ndash795 1996

[61] B Weber and E Schlicker ldquoModulation of dopamine releasein the guinea-pig retina by G119894- but not by G119904- or G119902-protein-coupled receptorsrdquo Fundamental and Clinical Pharmacologyvol 15 no 6 pp 393ndash400 2001

[62] J R Savinainen and J T Laitinen ldquoDetection of cannabinoidCB1 adenosine A1 muscarinic acetylcholine and GABA(B)receptor-dependent G protein activity in transducin-deactivated membranes and autoradiography sections ofrat retinardquo Cellular and Molecular Neurobiology vol 24 no 2pp 243ndash256 2004

[63] S Yazulla ldquoEndocannabinoids in the retina from marijuana toneuroprotectionrdquo Progress in Retinal and Eye Research vol 27no 5 pp 501ndash526 2008

[64] C A Opere W Zheng M Zhao J Lee K Kulkarni and SOhia ldquoInhibition of potassium- and ischemia-evoked [3H] D-aspartate release from isolated bovine retina by cannabinoidsrdquoCurrent Eye Research vol 31 no 7-8 pp 645ndash653 2006

[65] A Warrier and M Wilson ldquoEndocannabinoid signaling regu-lates spontaneous transmitter release from embryonic retinalamacrine cellsrdquo Visual Neuroscience vol 24 no 1 pp 25ndash352007

[66] S K Lim M J Park J C Lim et al ldquoHyperglycemia inducesapoptosis via CB 1 activation through the decrease of FAAH 1in retianl pigment epithelial cellsrdquo Journal of Cellular Physiologyvol 227 no 2 pp 569ndash577 2012

[67] Y Wei X Wang and L Wang ldquoPresence and regulation ofcannabinoid receptors in human retinal pigment epithelialcellsrdquoMolecular Vision vol 15 pp 1243ndash1251 2009

[68] YWei XWang F Zhao P-Q Zhao andX-L Kang ldquoCannabi-noid receptor 1 blockade protects human retinal pigmentepithelial cells from oxidative injuryrdquoMolecular Vision vol 19pp 357ndash366 2013

[69] A I Bondarenko ldquoEndothelial atypical cannabinoid receptordo we have enough evidencerdquo British Journal of Pharmacologyvol 171 no 24 pp 5573ndash5588 2014

[70] E Su M E Kelly S J Cringle and D Yu ldquoRole of endotheliumin abnormal cannabidiol-induced vasoactivity in retinal arteri-olesrdquo Investigative Opthalmology amp Visual Science vol 56 no 6pp 4029ndash4037 2015

[71] M D Caldwell S S-J Hu S Viswanathan H Bradshaw ME M Kelly and A Straiker ldquoA GPR18-based signalling systemregulates IOP in murine eyerdquo British Journal of Pharmacologyvol 169 no 4 pp 834ndash843 2013

[72] Y Sun and A Bennett ldquoCannabinoids a new group of agonistsof PPARsrdquo PPAR Research vol 2007 Article ID 23513 7 pages2007

[73] Y Chen Y Hu M Lin et al ldquoTherapeutic effects of PPAR120572agonists on diabetic retinopathy in type 1 diabetes modelsrdquoDiabetes vol 62 no 1 pp 261ndash272 2013

[74] S-F Fan and S Yazulla ldquoBiphasic modulation of voltage-dependent currents of retinal cones by cannabinoid CB1 recep-tor agonistWIN 55212-2rdquoVisual Neuroscience vol 20 no 2 pp177ndash188 2003

[75] A Straiker and J M Sullivan ldquoCannabinoid receptor activationdifferentially modulates ion channels in photoreceptors of thetiger salamanderrdquo Journal of Neurophysiology vol 89 no 5 pp2647ndash2654 2003

[76] S-F Fan and S Yazulla ldquoRetrograde endocannabinoid inhi-bition of goldfish retinal cones is mediated by 2-arachidonoylglycerolrdquo Visual Neuroscience vol 24 no 3 pp 257ndash267 2007

[77] P Lax G Esquiva C Altavilla and N Cuenca ldquoNeuropro-tective effects of the cannabinoid agonist HU210 on retinaldegenerationrdquo Experimental Eye Research vol 120 pp 175ndash1852014

[78] S Yazulla K M Studholme H H McIntosh and S-FFan ldquoCannabinoid receptors on goldfish retinal bipolar cellselectron- microscope immunocytochemistry and whole-cellrecordingsrdquoVisual Neuroscience vol 17 no 3 pp 391ndash401 2000

[79] D Kokona and K Thermos ldquoSynthetic and endogenouscannabinoids protect retinal neurons from AMPA excitotox-icity in vivo via activation of CB1 receptors involvement ofPI3KAkt and MEKERK signaling pathwaysrdquo ExperimentalEye Research vol 136 pp 45ndash58 2015

[80] C-Q Zhang H-J Wu S-Y Wang et al ldquoSuppression ofoutwardK+ currents byWIN55212-2 in rat retinal ganglion cellsis independent of CB1CB2 receptorsrdquo Neuroscience vol 253pp 183ndash193 2013

[81] I Amoros A Barana R Caballero et al ldquoEndocannabinoidsand cannabinoid analogues block human cardiac Kv43 chan-nels in a receptor-independent mannerrdquo Journal of Molecularand Cellular Cardiology vol 48 no 1 pp 201ndash210 2010

[82] A Barana I Amoros R Caballero et al ldquoEndocannabinoidsand cannabinoid analogues block cardiac hKv15 channels ina cannabinoid receptor-independent mannerrdquo CardiovascularResearch vol 85 no 1 pp 56ndash67 2010

[83] M R Lalonde C A B Jollimore K Stevens S Barnes andM E M Kelly ldquoCannabinoid receptor-mediated inhibition ofcalcium signaling in rat retinal ganglion cellsrdquoMolecular Visionvol 12 pp 1160ndash1166 2006

[84] T P Middleton and D A Protti ldquoCannabinoids modulatespontaneous synaptic activity in retinal ganglion cells rdquo VisualNeuroscience vol 28 no 5 pp 393ndash402 2011


[85] J E Slusar E A Cairns A-M Szczesniak H B Bradshaw ADi Polo and M E M Kelly ldquoThe fatty acid amide hydrolaseinhibitor URB597 promotes retinal ganglion cell neuroprotec-tion in a ratmodel of optic nerve axotomyrdquoNeuropharmacologyvol 72 pp 116ndash125 2013

[86] S Pinar-Sueiro J A Zorrilla Hurtado P Veiga-Crespo S CSharma and E Vecino ldquoNeuroprotective effects of topical CB1agonist WIN 55212-2 on retinal ganglion cells after acute rise inintraocular pressure induced ischemia in ratrdquo Experimental EyeResearch vol 110 pp 55ndash58 2013

[87] P S Amenta J I Jallo R F Tuma D C Hooper and MB Elliott ldquoCannabinoid receptor type-2 stimulation blockadeand deletion alter the vascular inflammatory responses totraumatic brain injuryrdquo Journal of Neuroinflammation vol 11article 191 2014

[88] J Palazuelos T Aguado M R Pazos et al ldquoMicroglial CB2cannabinoid receptors are neuroprotective in Huntingtonrsquosdisease excitotoxicityrdquo Brain vol 132 no 11 pp 3152ndash31642009

[89] J G Zarruk D Fernandez-Lopez I Garcıa-Yebenes et alldquoCannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophagemicroglialactivation concomitant to neuroprotectionrdquo Stroke vol 43 no1 pp 211ndash219 2012

[90] B Minke and B Cook ldquoTRP channel proteins and signaltransductionrdquo Physiological Reviews vol 82 no 2 pp 429ndash4722002

[91] D P Corey ldquoNew TRP channels in hearing andmechanosensa-tionrdquo Neuron vol 39 no 4 pp 585ndash588 2003

[92] M M Moran H Xu and D E Clapham ldquoTRP ion channels inthe nervous systemrdquo Current Opinion in Neurobiology vol 14no 3 pp 362ndash369 2004

[93] R G OrsquoNeil and S Heller ldquoThe mechanosensitive nature ofTRPV channelsrdquo Pflugers Archiv vol 451 no 1 pp 193ndash2032005

[94] R M Sappington and D J Calkins ldquoContribution of TRPV1 tomicroglia-derived IL-6 and NF120581B translocation with elevatedhydrostatic pressurerdquo Investigative Ophthalmology and VisualScience vol 49 no 7 pp 3004ndash3017 2008

[95] M A Dasilva K L Grieve J Cudeiro and C RivadullaldquoEndocannabinoid CB1 receptors modulate visual output fromthe thalamusrdquo Psychopharmacology vol 219 no 3 pp 835ndash8452012

[96] M Dasilva K L Grieve J Cudeiro and C Rivadulla ldquoAnan-damide activation of CB1 receptors increases spontaneousbursting and oscillatory activity in the thalamusrdquo Neurosciencevol 265 pp 72ndash82 2014

[97] B Jiang S Huang R de Pasquale et al ldquoThe matura-tion of GABAergic transmission in visual cortex requiresendocannabinoid-mediated LTD of inhibitory inputs during acritical periodrdquo Neuron vol 66 no 2 pp 248ndash259 2010

[98] B Jiang K Sohya A Sarihi Y Yanagawa and T TsumotoldquoLaminar-specific maturation of GABAergic transmission andsusceptibility to visual deprivation are related to endocannabi-noid sensitivity inmouse visual cortexrdquo Journal of Neurosciencevol 30 no 42 pp 14261ndash14272 2010

[99] W Sun L Wang S Li X Tie and B Jiang ldquoLayer-specificendocannabinoid-mediated long-term depression of GABAer-gic neurotransmission onto principal neurons in mouse visualcortexrdquo European Journal of Neuroscience vol 42 no 3 pp1952ndash1965 2015

[100] C-H Liu A J Heynen M G H Shuler and M F BearldquoCannabinoid receptor blockade reveals parallel plasticitymechanisms in different layers of mouse visual cortexrdquoNeuronvol 58 no 3 pp 340ndash345 2008

[101] Y Garkun and A Maffei ldquoCannabinoid-dependent potentia-tion of inhibition at eye opening in mouse V1rdquo Frontiers inCellular Neuroscience vol 8 article 46 2014

[102] I E Ohiorhenuan F Mechler K P Purpura A M SchmidQ Hu and J D Victor ldquoCannabinoid neuromodulation in theadult early visual cortexrdquo PLoS ONE vol 9 no 2 Article IDe87362 2014

[103] I Galve-Roperh T Aguado D Rueda G Velasco and MGuzman ldquoEndocannabinoids a new family of lipid mediatorsinvolved in the regulation of neural cell developmentrdquo CurrentPharmaceutical Design vol 12 no 18 pp 2319ndash2325 2006

[104] P Berghuis M B Dobszay X Wang et al ldquoEndocannabinoidsregulate interneuron migration and morphogenesis by transac-tivating the TrkB receptorrdquo Proceedings of the National Academyof Sciences of the United States of America vol 102 no 52 pp19115ndash19120 2005

[105] T Harkany M Guzman I Galve-Roperh P Berghuis LA Devi and K Mackie ldquoThe emerging functions of endo-cannabinoid signaling during CNS developmentrdquo Trends inPharmacological Sciences vol 28 no 2 pp 83ndash92 2007

[106] P A Fried B Watkinson and R Gray ldquoDifferential effects oncognitive functioning in 13- to 16-year-olds prenatally exposedto cigarettes and marihuanardquo Neurotoxicology and Teratologyvol 25 no 4 pp 427ndash436 2003

[107] A C Huizink and E J HMulder ldquoMaternal smoking drinkingor cannabis use during pregnancy and neurobehavioral andcognitive functioning in human offspringrdquo Neuroscience andBiobehavioral Reviews vol 30 no 1 pp 24ndash41 2006

[108] G A Richardson N L Day and L Goldschmidt ldquoPrenatalalcohol marijuana and tobacco use infant mental and motordevelopmentrdquoNeurotoxicology and Teratology vol 17 no 4 pp479ndash487 1995

[109] D Calvigioni Y L Hurd T Harkany and E KeimpemaldquoNeuronal substrates and functional consequences of prenatalcannabis exposurerdquo European Child amp Adolescent Psychiatryvol 23 no 10 pp 931ndash941 2014

[110] F Berrendero N Sepe J A Ramos V Di Marzo and J JFernandez-Ruiz ldquoAnalysis of cannabinoid receptor binding andmRNAexpression and endogenous cannabinoid contents in thedeveloping rat brain during late gestation and early postnatalperiodrdquo Synapse vol 33 no 3 pp 181ndash191 1999

[111] E Fride ldquoMultiple roles for the endocannabinoid systemduringthe earliest stages of life pre- and postnatal developmentrdquoJournal of Neuroendocrinology vol 20 supplement 1 pp 75ndash812008

[112] M Leonelli L R G Britto G P Chaves and A S TorraoldquoDevelopmental expression of cannabinoid receptors in thechick retinotectal systemrdquo Developmental Brain Research vol156 no 2 pp 176ndash182 2005

[113] H Cherif A Argaw B Cecyre et al ldquoGPR55 participates to thedevelopment of the nervous systemrdquo in Proceedings of the 43rdAnnualMeeting of the Society for Neuroscience San Diego CalifUSA 2013

[114] A Argaw G Duff N Zabouri et al ldquoConcerted action of CB1cannabinoid receptor and deleted in colorectal cancer in axonguidancerdquo The Journal of Neuroscience vol 31 no 4 pp 1489ndash1499 2011


[115] G Duff A Argaw B Cecyre et al ldquoCannabinoid receptor CB2modulates axon guidancerdquo PLoS ONE vol 8 no 8 Article IDe70849 2013

[116] A T Guy Y Nagatsuka N Ooashi et al ldquoGlycerophospholipidregulation of modality-specific sensory axon guidance in thespinal cordrdquo Science vol 349 no 6251 pp 974ndash977 2015

2 Neural Plasticity

marijuana include a reduction in Vernier and Snellen acu-ity alterations in color discrimination and an increase inphotosensitivity [13 14] Some anecdotal reports also showedthat Jamaican fishermen smoke marijuana to improve dimlight vision when fishing at night [15] These results havebeen corroborated by another study that measured moreprecisely the night vision of Moroccan fishermen usingcannabis to improve visual perception [16]The authors notedincreased night vision following THC or cannabis ingestionand suggested that these effects were produced locally inthe retinaThese intriguing findings have certainly fascinatedvarious researchers who then began to study the expression ofthe eCB system in the visual system with a focus on the adultretinaWhile still scarce there are now increasing evidence oftransient receptor and enzymatic machinery expression dur-ing development Section 2 and Section 3 of this review willdescribe the expression (Section 2) and function (Section 3)of eCBs in the adult retina whilst Section 4will focus on theseduring development (Section 4)

2 Cannabinoid Expression inthe Visual System

21 Ocular Tissues It is well established that marijuana con-sumption induces vasodilatation in conjunctiva noticeableby a reddish color change in the eyes and a reduction inintraocular pressure [12] It was first believed that marijuanaexerted its effects systemically through the central nervoussystem (CNS) However it became evident that cannabinoidscan act locally on cannabinoid receptors present in variouscell types in the eye [17] Physiological and biochemicalstudies demonstrated the presence of the eCB system invarious regions of ocular tissues The CB1R mRNA is foundin the ciliary body of rat bovine and human as well as inthe trabecular meshwork in bovine and human [18ndash21] CB1Ris also detected in the nonpigmented ciliary epithelium inhuman and bovine tissues and conjunctival epithelium inmouse and human [19 22]The bovine corneal epithelial cellsexpress among others CB1R MAGL 120572120573 hydrolase domain6 (ABHD6) 120572120573 hydrolase domain 12 (ABHD12) and N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD)mRNA [23] Furthermore AEA and 2-AG as well as otherN-acyl ethanolamides such as palmitoylethanolamide (PEA)are present in human ocular tissues except for the lens [2024]

22 Adult Retina

221 Endocannabinoids The two major eCBs (AEA and 2-AG) are present in the retina of adult rodents [17] bovines[25] and humans [20] Most of the studies comparing AEAto 2-AG expression in the retina concluded that 2-AG levelsare significantly higher than AEA thus human and bovineretinas contain 25 times more 2-AG compared to AEA[20 25 26] PEA was detected in the rat and human andoleoylethanolamide (OEA) another endocannabinoid-likeN-acyl ethanolamide was also measured in the rat retina[17] In human 2-AG is mostly produced in the retina while

Table 1 Endocannabinoid levels in the adult retina of variousspecies

Endocannabinoids Concentration(pmolg) Species

2-arachidonoyl glycerol(2-AG)

297013931600

Rat [17]Human [20]Bovine [25]

Anandamide (AEA)

Under detection level200003664

Rat [17]Rat [26]

Human [20]Bovine [25]

Palmitoylethanolamide(PEA)

130200

Rat [17]Human [20]

Oleoylethanolamide (OEA) 55 Rat [17]

AEA and PEA are mainly expressed in the iris [20] Theendocannabinoid levels in the retina are presented in Table 1

The content of eCBs varies in certain disease statessuggesting the importance of eCBs in maintaining ocularhomeostasis For instance 2-AG levels decrease in the ciliarybody of patients with glaucoma [20] but increase in the irisof patients with diabetic retinopathy [24] Similarly PEAlevels are lower in the ciliary body and the choroid ofglaucomatous human retinas [20] but higher in the ciliarybody of diabetic retinopathy human retinas [24] Patientswith age-related macular degeneration (AMD) and diabeticretinopathy also showed widespread increases of AEA levelsin the retina choroid ciliary body and cornea [24] It isbelieved that the upregulation of eCBs in these disorders maycontribute to cell protection in part by the anti-inflammatoryand neuroprotective properties of eCBs [24]

222 Cannabinoid Receptors CB1R was extensively studiedin the retina of various species using techniques such asin situ hybridization reverse transcription polymerase chainreaction (RT-PCR) Western blot or immunohistochemistryCB1R was first localized in the ganglion cell layer (GCL) andinner nuclear layer (INL) of the rat retina [27] Since thenCB1R expression was detected in the retinas of human mon-keymouse rat chick salamander and goldfishwith a similarlabeling in the outer plexiform layer (OPL) inner plexiformlayer (IPL) and GCL [17 22] A schematic illustration of themouse retina organization is presented in Figure 1 Retinalprotein distribution of CB1R is presented in Table 2 and itsexpression for different species is illustrated in Figure 2

The cannabinoid receptor type 2 (CB2R) distribution inthe retina has been less extensively studied than CB1R Thiscould be explained in part by the lack of specific markers forCB2R [28ndash30] and by initial reports revealing an expressionpattern restricted to immune cells It was first believed thatCB2R was not expressed in the embryonic and adult ratretina [18 27] Then CB2R mRNA localization was shownin photoreceptors INL and GCL of the rat retina [31]More recently protein expression of CB2R was detected inretinal pigment epithelium (RPE) inner segments of thephotoreceptors and horizontal and amacrine cells of the ratretina [32] Furthermore a recent report localized CB2R in

Neural Plasticity 3

GCL

IPL

INL

OPL

ONL

OSIS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS



Retinal cells

Photoreceptors











Retinal cells

Photoreceptors



Bipolar cells



Muller cells




4 Neural Plasticity

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Human Mouse

Primate Rat

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS






Neural Plasticity 5

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Mouse Primate

Rat






6 Neural Plasticity











Neural Plasticity 7








8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































Neural Plasticity 3

GCL

IPL

INL

OPL

ONL

OSIS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS



Retinal cells

Photoreceptors











Retinal cells

Photoreceptors



Bipolar cells



Muller cells




4 Neural Plasticity

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Human Mouse

Primate Rat

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS






Neural Plasticity 5

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Mouse Primate

Rat






6 Neural Plasticity











Neural Plasticity 7








8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































4 Neural Plasticity

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Human Mouse

Primate Rat

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS






Neural Plasticity 5

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Mouse Primate

Rat






6 Neural Plasticity











Neural Plasticity 7








8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































Neural Plasticity 5

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

G

CBC

A

H

GCL

IPL

INL

OPL

ONL R

G

A

C

RBC

H

M

OS

IS

Mouse Primate

Rat






6 Neural Plasticity











Neural Plasticity 7








8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































6 Neural Plasticity











Neural Plasticity 7








8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































Neural Plasticity 7








8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































8 Neural Plasticity







Neural Plasticity 9












6 Conclusion




References



























































































































Neural Plasticity 9












6 Conclusion




References





























































































































6 Conclusion




References



























































































































expression and function of the endocannabinoid …...expression and function of the endocannabinoid...

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