serotonina e receptores
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The Hippocampus and Serotonin
Receptors:
A table of contents
• Characteristics of the Raphe Nuclei
• Function of the Raphe Nuclei
• Malfunction of the hippocampus in depression
• Serotonin Receptors (5-HTRs) and Signal
Transduction
• 5-HT innervations in the hippocampus
• Signal Transduction of the pyramidal cells
• Summary
1
A table of contents
• Characteristics of the Raphe Nuclei
• Function of the Raphe Nuclei
• Malfunction of the hippocampus in depression
• Serotonin Receptors (5-HTRs) and Signal
Transduction
• 5-HT innervations in the hippocampus
• Signal Transduction of the pyramidal cells
• Summary
2
3
Major depression is one of the most common mood
disorders(over 20% of U.S. for over 18 yo during life, NIH).
Symptoms: A loss of interest, Change of mood representations,
Impairment of social, occupational, or educational function,
Sleep problem(Insomnia or hypersomnia), indecisive, Suicidality,
Worthlessness(DSM-IV, 1994)
Why Serotonin?:
Low levels of serotonin in the patients(Serotonin-deficiency
theory)[Lacasse, Plos Med., 2005]
Strong evidence:
Selective Serotonin Reuptake Inhibitors(SSRI) -> induction of
extracellular serotonin increase
• Major antidepressant drugs(about -70%)
However, detailed etiology is still unknown.
What is depression? And What’s the cause
Aim of This Independent StudySome discrepancies:
1) A slow effect of SSRI on mood even after acute
treatment[Harmer, BJPsychiatry, 2009]
2) SSRI is not completely effective(Dopamine theory, BDNF
theory)[Dunlop, Arch Gen psychiatry, 2006;Trivedi, The New England Journal
of Medicine, 2006]
On the other hand….(several indication)
1)15 subgroups of Serotonin (5-HT) receptor family and
different effect on neurons
2) Region-dependent distribution of the receptors
3) Strong Serotonergic innervations related with several brain
regions in the depression patients(the hippocampus, the basal
ganglia, and the amygdala).
4
Serotonergic projections
Presumption of depression
Presumption:
• Neuronal network might cause
differential effect on multiple brain
regions due to different receptor
types of serotonin.
Purpose of this seminar
• Summary of detailed survey of
serotonin innervations
5
A table of contents
• Characteristics of the Raphe Nuclei
• Serotonin Receptors (5-HTRs) and Signal
Transduction
• Malfunction of the hippocampus in depression
• 5-HT innervations in the hippocampus
• Signal Transduction of the pyramidal cells
• Summary
6
Serotonin (5-HT)
• One of monoamine
neurotransmitters
• 5-HT, tryptophan, and
melatonin are related
metabolites.
• Breathing rhythms, heart
rate, locomotion, circadian
rhythms, emotions, and
neurogenesis.
7
General Characteristics of Raphe Nuclei
Classification:
The raphe nuclei: serotonin (5-HT) containing neuron clusters(Midline of the brainstem)
• Subdivisions in rats:
B1: Raphe Pallidus, B2: Raphe Obscurus, B3: Raphe magnus, B4: Raphe
Obscurus(dorsolateral part), B5: Raphe Pontis, B6: Dorsal Raphe Nucleus(caudal
part), B7: Dorsal Raphe Nucleus(Principal part), B8:Median Raphe Necules(Main
party), B9:Dorsal Pontine Tegmentum
• 85% of 5-HT neurons in Rostral(B7, B8) part of human brains[Hornung, J. Chemi.
Neuroana. 2003]
8[Siegel, 2008]
Fig 2 Caudal
part(B1-3),
Rostral(B7, B8)
[Stahl S., 1996]
revised by CNS
General Characteristics of Raphe Nuclei
9
[Vertes and Linley, International Congress Series,
2007]
Dorsal Raphe(DR) projections in rat:
the ventral tegmental area(VTA), the substantia
nigra pars compacta(SNc), some regions of
hypothalamus, amygdala complexes, dorsal and
ventral striatum, lateral septum(LS), the
entorhinal(EC), medial orbital (MO) and the medial
prefrontal cortex (mPFC), the hippocampus.
(anterograde tracer with PHA-L[Vertes and Linley,
2007])
Median Raphe(MR) projections in rat:
the interpeduncular nucleus, VTA, medial
mammillary nucleus, parts of the midline and
intralaminar thalamus, the lateral habenula,
septum, ventral striatum(Nucleus accumbens),
the hippocampus, medial septum (MS)[Vertes
J.Comp. Neurol, 1999; Vertes and Linley, 2007].
DR: cell size(30-
40um), fusiform,
darkly stained
MR: cell size(10-
12um), oval,
lightly
stained[Verte.,
2007]
Blue: dopaminergic nuclei
Red: Amygdala related
Orange: Basal Ganglia
Brown: hippocampus
Reciprocal links between DRN and MRN
11
DRN
MRN
“We are brothers and friends, but…”
Glu application into the DRN[Mokler, 2009]
unknown
Glu application into the MRN[Mokler, 2009]
Mutual connections in rats and hamster[Vertes and et al., 1988, 1991,
1999; Tisheler and Morin, Brain Res., 2003]
The mean of extracellular 5-HT: DRN(15.6 ± 2.4
fmol/20ul = 0.78 ± 0.12 nmol/l; n = 16), MRN(10.6 ± 1.3
fmol/20ul = 0.53 ± 0.065 nmol/l; n=16)[Mokler, Brain Res., 2009]
Putative Firing rate of 5-HT neurons: DRN(1.34 ± 0.09
Hz), MRN(0.54 ± 0.05 Hz)[Judge., etal, Neurochemi., 2006]
DRN affects MRN, but MDR does not affect much.
Function of DRN -Patience and Impulsivity-
Patience and Impulsivity
1. Activation 5-HT Neurons in DRN
during waiting delayed rewards
2. Negative correlation between 5-HT
activity and Wait Error.
Omission trials counted by removal of nose-
poking.
12[Miyazaki et al., Mol Neurobiol, 2012]
Disruption of theta rhythms by stimulation of
Serotonergic neurons in MRN
14
MS – DBB: Medial septum-diagonal band of Broca
LHA: Lateral hypothalamic area
Hypocretin: Orexin
Theta Rhythms (4 - 10 Hz): relationship with memory
consolidation in the hippocampus and possible to be
induced by stress
Induction of Inescapable foot shook by MS-DBB
Prevention of theta rhythms by lesion of MS – DBB[]
[Hsiao et al., Behavioral Brain Resarch,2012]
(cited from UCLA facility)
[Hsiao et al., Behavioral B. Res., 2013]
A table of contents
• Characteristics of the Raphe Nuclei
• Function of the Raphe Nuclei
• Malfunction of the hippocampus in depression
• Serotonin Receptors (5-HTRs) and Signal
Transduction
• 5-HT innervations in the hippocampus
• Signal Transduction of the pyramidal cells
• Summary
15
Malfunction of hippocampal neurogenesis hypothesis
16
Slow effect of SSRI or Antidepressant
drugs (AD) -> Morphological changes
(?)
[Berton, Nature Neuro., 2006]
• Brain-Derived Neurotrophin Factor (BDNF) -> Induction of
Neuro-proliferation -> Promotion of Neurogenesis
• Decrease of BDNF by stress in hippocampus[Smith et al.,
1995]
• BDNF mRNA promotion by AD drugs[Nibuya, J. Nuro., 1995]
Chronic ADs increase
neurogenesis in Rat
hippocampus[Malberg, J.
Neuro., 2000]
Measurement of helplessness and anxiety
17
The Forced Swim Test:
Check immovability of mice
Normal: Try to avoid water
Abnormal: Be quiet.
Interpretation: immovability shows despair.
The Novelty Suppressed Feeding (NSF)
test
Check amount of foods in a novel
environment after removal of feeding.
Interpretation: hesitation for rewards shows
level of anxiety of a new environment.
Malfunction of hippocampal neurogenesis hypothesis
18
The novelty suppressed feeding[Kuteeva, Springer, 2010].
Selective inhibition of neurogenesis -> Prevention of
Antidepressant Drugs effects[Santarelli et al., Science,
2003]
[Bremner JD., CNS, 2002]
Hippocampal volume reduction in
depression patients
A table of contents
• Characteristics of the Raphe Nuclei
• Function of the Raphe Nuclei
• Malfunction of the hippocampus in depression
• Serotonin Receptors (5-HTRs) and Signal
Transduction
• 5-HT innervations in the hippocampus
• Signal Transduction of the pyramidal cells
• Summary
19
Serotonin Receptors
20
Subtypes Agonists Antagonists G protein Localization Function
5-HT1A Tetalin, 5-MeO-
DMT, BAY, 8-OH-
DOAT
Spiperone,
WAY-100135
Gi(AC↓,
open K+),
Go(close
Ca2+)
Hippocumpus,the lateral septum,entorhinal
and cingular cortices, dorsal raphe nucleus
Autoreceptor,
Heteroreceptor
5-HT1B (unselective)
TFMPP,
CGS12066B,Sumat
riptan, L694247
Isamoltane,
GR-55562, SB
224289, SB-
236057
Gi(AC↓) SN,globus pallidus,caudate
putamen,ventral pallidum,entopeduncular
nucleus,hippocampus, cortex,VTA
Autoreceptor
5-HT1D Sumatriptan, PNU
109291, BRL 15572
GR-127935 Gi(AC↓) SN,globus pallidus,caudate putamen,ventral
pallidum,entopeduncular
nucleus,hippocampus, cortex,VTA
Autoreceptor
5-HT1E Gi(AC↓) The caudate,putamen amygdala,and cortical
areas(Bruinvels, 1994)
5-HT1F Gi(AC↓) hippocumpus cortical areas
5-HT2A DOI, DOB, α-Me5-
HT
ritanserin(vged
o ,1989)
Gq(PLC)↑ Cortex, claustrum, hippocampus,
hypothalamus, basal ganglia
Post synaptically
expressed
5-HT2C SB-243213(Blackbu
rn et al., 2002)
Mesulergine,
SB-242084,
RS-102221
Gq(PLC)↑ the chroid plexus, the frontal cortex,the
limbic system,hippocumpus,septum,hypot
halamus, striatum,nucleus
accumbens,rhombencephalon,spin al cord [Filip, 2009;Hoyer,
2002]
21
Subtypes Agonist
s
Antagonists G protein Localization
5-HT3 α-Me-5-
HT
DAU 6215
Zacopride, Odanserton,
Granisotron
Zatosetron
None(Ion channels-influx
Na+, Ca2+, efflux K+)
the caudal medulla, forebrain, SN, N. AC,
prefrontl cortex, striatum
GABA-containing cells in neocortex, olfactory
cortex, hippocampus, amygdala
5-HT4 SC-
53116
SDZ-205557
GR-125487
Gs(AC↑) limbic regions, the olfactory system, striatum,
medial habenula, hippocampus
5-HT5A Gi/o(AC↓) Hippocampus, hypothalamus, olfactory bulb,
cortex, thalamus, striatum, pons
5-HT5B ? Habenula, raphe nucleui, hippocampus(in
rodents); pseudogene(in humans)
5-HT6 Lisuride, Colozapine
SB271046
Gs(AC↑) Striatum, olfactory tubercle, N. Acc,
5-HT7 LSD Clozapine, Amitryptline Gs(AC↑) hypothalamus, thalamus, brain stem, striatum,
cerebral cortex.
[Filip, 2009;Hoyer, 2002]
Serotonin receptors and Signal Transduction
a
22
[Berumen et al., The Scientific World Journal,2012]
Serotonin Receptors and Signal Transduction
• a
23[Berumen et al., The Scientific World Journal,2012]
Serotonin Receptors and Signal Transduction
• a
24
[Berumen et al., The Scientific World Journal,2012]
25
26
A table of contents
• Characteristics of the Raphe Nuclei
• Function of the Raphe Nuclei
• Malfunction of the hippocampus in depression
• Serotonin Receptors (5-HTRs) and Signal
Transduction
• 5-HT innervations in the hippocampus
• Signal Transduction of the pyramidal cells
• Summary
27
Hippocampus and 5-HT Ascending
Projections
CC: Central Gray
GCL: granule cell layer
Mo: Molecular layer of
Dentate Gyrus
PCL: Pyramidal Layer
SLM: Stratum lacunosum-
moleculare
SR: Stratum radiatum
SOr: Stratum oriens
28
Mouse Brain(cited from NeuroDigi)
PHA-L 5-HT fibers[Morin et al., 1999] PHA-L MR fibers to hippocampus[Morin et al., 1999]
PHA-L MR fibers in ventral Hippocampus[Vertes, 1999]
MR fibers in
dorsal
Hippocampu
s[Vertes,
1999]
Serotonin Receptor Expression in the mouse
hippocampus
• a
29
5-
HTR
Hippo. Localization
1A granular, pyramidal N., and some glia
(Presynaptic R as well)
1B Presynaptic N. of DRN or MRN
2A granular, pyramidal, and astrocytes
2C CA3 pyramidal.
3A CA2 and C3 Pyramidal N.
4 Cholinergic axon
5A Astrocytes
5B CA1 pyramidal cells
7 CA1 neurons
Serotonin Receptor Expression in the mouse
hippocampus
• a
30
GCL: Granule cell layer, Glu
ML: molecular layer,
Hilus:
• a
31[Berumen et al., The Scientific World Journal,2012]
SSRI induces
neurogenesis[Santralli, 2003]
-> 5-HT increase in DG.
Q1. Which receptor is dominant?
Assumption(As) . Maybe 5-HT1AR,
and linking to inhibition of AC.
• a
32[Berumen et al., The Scientific World Journal,2012]
SSRI induces
neurogenesis[Santralli, 2003]
-> 5-HT increase in DG.
Q1. Which receptor is dominant?
Assumption(As). Maybe 5-HT1AR,
and linking to inhibition of AC.
Q2. Express where?
• a
33[Berumen et al., The Scientific World Journal,2012]
SSRI induces
neurogenesis[Santralli, 2003]
-> 5-HT increase in DG.
Q1. Which receptor is dominant?
Assumption(As). Maybe 5-HT1AR,
and linking to inhibition of AC.
Q2. Express where?
a) Induction of neurogenesis by 5-
HT1A agonist in DG[Grabiec, 2009].
b) Inhibition of cell proliferation by
5-HT1A antagonist[Radley, JJ.,
2002].
• a
34[Berumen et al., The Scientific World Journal,2012]
SSRI induces
neurogenesis[Santralli, 2003]
-> 5-HT increase in DG.
Q1. Which receptor is dominant?
Assumption(As). Maybe 5-HT1AR,
and linking to inhibition of AC.
Q2. Express where?
a) Induction of neurogenesis by 5-
HT1A agonist in DG[Grabiec, 2009].
b) Inhibition of cell proliferation by
5-HT1A antagonist[Radley, JJ.,
2002].
As:
1. GABA > Pyramidal
How b) happen?
• a
35[Berumen et al., The Scientific World Journal,2012]
SSRI induces
neurogenesis[Santralli, 2003]
-> 5-HT increase in DG.
Q1. Which receptor is dominant?
Assumption(As). Maybe 5-HT1AR,
and linking to inhibition of AC.
Q2. Express where?
a) Induction of neurogenesis by 5-
HT1A agonist in DG[Grabiec, 2009].
b) Inhibition of cell proliferation by
5-HT1A antagonist[Radley, JJ.].
As:
1. GABA > Pyramidal
How b) happen?
2. Pyramidal > GABA
5-HT1A G protein activates cAMP?
• a
36[Berumen et al., The Scientific World Journal,2012]
SSRI induces
neurogenesis[Santralli, 2003]
-> 5-HT increase in DG.
Q1. Which receptor is dominant?
Assumption(As). Maybe 5-HT1AR,
and linking to inhibition of AC.
Q2. Express where?
a) Induction of neurogenesis by 5-
HT1A agonist in DG[Grabiec, 2009].
b) Inhibition of cell proliferation by
5-HT1A antagonist[Radley, JJ.].
As:
1. GABA > Pyramidal
How b) happen?
2. Pyramidal > GABA
5-HT1A G protein activates cAMP?
3. Other receptors? Other G
proteins?
4. 5-HT increase in DG?
Signal Transduction of Pyramidal neurons
37
Unknow
n
[Dumen et al., 2012]
Summary
• 1. Serotonergic neurons project to the basal
ganglia, the amygdala complex, the
hippocampus, and others.
• 5-HT affect neurogenesis as well as anxiety.
• Differential 5-HTRs’ expression in
hippocampus.
• A causal receptor is still unknown.
38
39Dance of the Rats[17c, Germany]
Discussion Time
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