See:

Chapter 13. Modulation of synaptic transmission:Second messengers.

“Principles of Neuroscience” Kandel ER et al4th edition, 2000, McGraw-Hill

Page 229

Fast: GABA, glutamate, acetylcholine

Slow: biogenic aminesDopamineSerotonin/5-HTNEAcetylcholinePeptides

OUT

IN

Cl-

Cl-

Na+

Na+

GABAA receptor Glutamate/AMPAreceptor

GA

BA

Gl

u

Inhibition Excitation

Simple circuits

Feed-forward inhibition

Negative feedback

Feedback inhibition

Neocortex

Interneuron - uses GABA

Pyramidal neuron- uses glutamate

Information integrationcognition, thought,

mood, emotion

Cerebral cortex

Sensory input Motor output

acetylcholine norepinephrineserotonin dopamine histamine

Information integrationcognition, thought,

mood, emotion

Cerebral cortex

Sensory input Motor output

Arousal:

1. Processing signals relate to plain & pleasure. Regulatingbody homeostasis

4. Emotion and feeling5. Attention6. Wakefulness & sleep5. learning

The construction of consciousness.

Fast synaptic transmission -ligand-operated ion channelsthe hardware of the brain

Slow synaptic transmission: the software that controlsfast transmission

Ionotropic and metabotropic receptors

Fast

Ion flow in/out

milliseconds

Slow

Second messenger cascades

seconds

1/1000 of a second !

Out

In

G

7 transmembrane domain receptor

2nd messengers

NH2

COOH

Ionotropic

Metabotropic

The monoamines

Dopamine

Epinephrine (adrenergic)

Norepinephrine (noradrenergic)

Serotonin

Second messengers

Protein kinases

Transcription FactorsCell nucleus

Ion pumps

Ion channels

Neurotransmitterreceptors

Neurotransmitterreceptors

7-transmembrane-domain receptors

Glutamate

Ca2+

Ca2+-dependentKinases/phosphatases

Down-stream substrates

Gene expression

Short-term synaptic modification Long-term synaptic modification

cAMP

PKAHist

DA

NE ACh

5-HT

HistPKC

IP3 + DG

GluR

1

D1

H2

M1

5-HT2C

H1

Excitatory input

Neuromodulatory inputs

Neuromodulatory inputs

Particular modulator transmitters should not be regardedas purely excitatory or inhibitory.

Their exact action depends on context.

On the same cell, they can be either excitatory or inhibitorydepending on the state of the cell.

The Nobel prize in 2000 went to three neuroscientistsfor working out the role of biogenic amines/monoamines in the nervous system:

Arvid Carlsson

Paul Greengard

Eric Kandel

The Nobel Prize in 2000 went to three neuroscientistsfor working out the role of biogenic amines/monoamines in the nervous system:

Arvid Carlsson (dopamine/l-dopa therapy)

Paul Greengard (role of phosphorylation)

Eric Kandel (serotonin in learning & memory)

Carlsson, A (2001). A paradigm shift in brain research. Science, vol. 294, p1021-1024

**Greengard, P (2001). The neurobiology of slow synaptic transmission.Science, vol. 294, p1024-1030

**Kandel, ER (2001). The molecular biology of memory storage: adialogue between genes and synapses.Science, vol. 294, p1030-1038

Catecholamines

Norephinephrine

A synapse that uses norepinephrine (NE)

Reuptake of NE

Monoamine oxidase, located on outer membraneof mitochondria; deaminates catecholamines free innerve terminal that are not protected by vesicles

Selective inhibitor,reboxetine Cocaine blocks the NET

Antidepressant

MAO Inhibitors

Stimulant

NE potentiation of responses to GABA

Purkinje cells

PO4

Cl-

Cl-

GABACl-

Cl- Cl- Cl- Cl- Cl-

GABA

Out

In

time

GABAresponse

GABA

GABA + NE

GABA + cAMP

Noradrenergic potentiation of cerebellar Purkinje cell responsesto GABA: cAMP as intracellular intermediary.

1

NE

Gs AC

ATP

cAMP

PKA reg

PKA cat

PO4

GABAA receptor-adrenergicreceptor

PO4

Cl-

Cl-

GABACl-

Cl- Cl- Cl- Cl- Cl-

GABA

Out

In POSTSYNAPTIC MODULATION

Why does a small amount of stress help you learn better?

-adrenergics and memory

Presynaptic Postsynaptic

Before LTP

After LTP

More glutamate receptors= bigger response

After LTP

More glutamate receptors= bigger response

After several hours…….

Presynaptic Postsynaptic

LTP decays

Unless -adrenergic activation of postsynaptic cell takes place…

NE

Glu

cAMPPKA

Inhibition ofprotein phosphatase I

Active during memoryformation

Stabilization of LTP

-adrenergic receptor activation helps memories

-better memories when you are paying attention because of higher emotional stimulation

SEROTONIN5-HT

PRESYNAPTICMODULATION

See:

Chapter 63. Cellular mechanisms of learning.Page 1247.“Principles of Neuroscience” Kandel ER et al4th edition, 2000, McGraw-Hill

See also, Chapter 13, Figure 13-12 in Kandel et al

Or

Chpater 50. Learning and memory: basic mechanisms.Page 1275Fundamental Neuroscience, second edition,Squire LR et al, 2003, Academic Press

Serotonin - a chemical manifestation of personality

High level of serotonin: compulsivesobsessive-compulsive disorderse.g. compulsive hand-washing

Low levels of serotonin: depression, suicide.

Listening to Prozac, P.D. Kramer, 1993

Humans

The 5-HT neurons in the brain

A synapse that uses serotonin/5-HT

Re-uptake of 5-HT/serotonin

Fluoxetine/Prozac blocks the SERT

Treatment of depression.anxiety disorders, obsessive-compulsive disorders

Genetic variation in the gene promoter region of the serotonin transporter.

risk factor for anxiety, alcoholism, mood disorders

slight differences in level of expression

Catecholamines

Dopamine

Dopamine pathways in the brain

Dopamine pathways do many things:Control flow of blood through the brain Motor control (nigrostriatal) system

Behavioural controlDopamine is the brain’s motivational chemical. It works onglutamate synapses to modulate their excitability.

A shortage of brain dopamine causes an indecisivepersonality, unable to initiate even the body’s ownmovement. Parkinson’s disease. Time stops.L-DOPA therapy. ‘Awakenings’ film. (Oliver Sachs)

Excess dopamine, more arousal. Attention defecit disorder. May cause schizophrenia.Dopamine’s action is essential for drug addiction.

Rabbits treated withreserpine

The same rabbits 15 minutes after treatment withL-DOPA

A. Carlsson, 1960See Science, vol 294, p1002, 2 November 2001

L-DOPA rescues Parkinsonian rabbits

DARP-32

Dopamine and cAMP-regulated phosphoproteinMolecular weight, 32 kDa

DARP-32 is a molecular integrator

Overlapping cell

Neural ensembles

Neocortexneurons

Dop

neocortex

Substantianigra

1

4

3

2

Dop

4

2

1 3

Dop

Dop

neocortex

Substantianigra

neocortex

Substantianigra

Parkinson’s disease. No dopamineNo neural ensembles can be selected

DA

neocortex

Substantianigra

Schizophrenia?Active neural ensembles too extended?

Other neuromodulators (NE, serotonin) probablywork in a similar way to dopamine

They assist with the selection/maintenance of differentneural ensembles.

Molecular actions of dopamine

Polymorphisms of genes involved in aminergic (dopamine/serotonin) neurotransmission

Effects on personality?

Dopamine D4 receptor - novelty seekingPromoter of serotonin transporter gene - harm avoidance/anxiety

D4 dopamine receptor

16 amino acid repeat sequence present in twoto 11 copies - minisatellite phrase

D4 dopamine receptor

The larger the number of repeats, the more ineffective is the dopamine D4 receptor in signalling

The larger the number of loop 3 repeats, the more ineffective the dopamine D4 receptor in signalling

“Long” D4DR genes imply low responsiveness to dopamine“short” D4DR gene imply high responsiveness

The idea People with “long” D4DR genes have low responsiveness to dopamine, so they need to take a more adventurous approach tolife to get the same dopamine “buzz” that short-gened people get from simple things.

Obviously, this is just one possible factor of many.Don’t oversimplify!

Neuromodulators

Slow synaptic transmission

William.Wisden@urz.uni-heidelberg.de

Alan@uni-hd.de

Alan Summerfield