serotonina e receptores

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





Transduction



• 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



Transduction




• 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





Transduction



• 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





Transduction



• 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]

A table of contents





Transduction



• 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


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


SSRI induces




Assumption(As). Maybe 5-HT1AR,


Q2. Express where?

• a


SSRI induces






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


SSRI induces






Q2. Express where?




5-HT1A antagonist[Radley, JJ.,

2002].

As:

1. GABA > Pyramidal

How b) happen?

• a


SSRI induces






Q2. Express where?




5-HT1A antagonist[Radley, JJ.].

As:

1. GABA > Pyramidal

How b) happen?

2. Pyramidal > GABA

5-HT1A G protein activates cAMP?

• a


SSRI induces






Q2. Express where?




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

serotonina e receptores

Science

different effect

low levels of serotonin

total cons of serotonin

raphe nucleimalfunction

raphe nucleifunction

differential effect

multiple brain regions

slow effect of ssri