See: Chapter 13. Modulation of synaptic transmission: Second messengers. “Principles of Neuroscience” Kandel ER et al 4th edition, 2000, McGraw-Hill Page 229

Fast: GABA, glutamate, acetylcholine Slow: biogenic amines Dopamine Serotonin/5-HT NE Acetylcholine Peptides

Inhibition Excitation OUT Cl- Na+ Cl- Na+ IN GABA Glu GABAA receptor Glutamate/AMPA receptor Inhibition Excitation IN

Simple circuits

Feed-forward inhibition

Negative feedback Feedback inhibition

Neocortex Interneuron - uses GABA Pyramidal neuron - uses glutamate

Cerebral cortex Sensory input Motor output Cerebral cortex Information integration cognition, thought, mood, emotion Cerebral cortex Sensory input Motor output Information integration cognition, thought, mood, emotion Cerebral cortex Sensory input Motor output acetylcholine norepinephrine histamine serotonin dopamine

Arousal: Processing signals relate to plain & pleasure. Regulating body homeostasis Emotion and feeling Attention Wakefulness & sleep 5. learning The construction of consciousness.

Fast synaptic transmission -ligand-operated ion channels the hardware of the brain Slow synaptic transmission: the software that controls fast transmission

Ionotropic and metabotropic receptors Fast Ion flow in/out milliseconds Slow Second messenger cascades seconds 1/1000 of a second !

7 transmembrane domain receptor Out NH2 In 2nd messengers G COOH

Ionotropic Metabotropic

The monoamines Dopamine Epinephrine (adrenergic) Norepinephrine (noradrenergic) Serotonin

Transcription Factors Neurotransmitter receptors Neurotransmitter receptors Ion pumps Second messengers Protein kinases Transcription Factors Cell nucleus Ion channels

7-transmembrane-domain receptors

Excitatory input Glutamate Neuromodulatory Neuromodulatory inputs ACh GluR NE b1 M1 Ca2+ 5-HT DA IP3 + DG D1 Ca2+-dependent Kinases/phosphatases cAMP PKC 5-HT2C Hist Hist PKA Down-stream substrates H2 Gene expression H1 Short-term synaptic modification Long-term synaptic modification

Particular modulator transmitters should not be regarded as purely excitatory or inhibitory. Their exact action depends on context. On the same cell, they can be either excitatory or inhibitory depending on the state of the cell.

Arvid Carlsson Paul Greengard Eric Kandel The Nobel prize in 2000 went to three neuroscientists for working out the role of biogenic amines/monoamines in the nervous system: Arvid Carlsson Paul Greengard Eric Kandel

Arvid Carlsson (dopamine/l-dopa therapy) The Nobel Prize in 2000 went to three neuroscientists for 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: a dialogue between genes and synapses. Science, vol. 294, p1030-1038

Catecholamines Norephinephrine

A synapse that uses norepinephrine (NE)

Reuptake of NE MAO Inhibitors Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles Antidepressant Selective inhibitor, reboxetine Stimulant Cocaine blocks the NET Reuptake of NE

NE potentiation of responses to GABA Purkinje cells

Out Cl- GABA Cl- Cl- Cl- Cl- Cl- Cl- GABA PO4 In

GABA + cAMP GABA + NE GABA GABA response time Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cAMP as intracellular intermediary.

NE GABAA receptor b-adrenergic receptor AC PO4 Gs cAMP PKA reg PKA cat ATP

Out Cl- GABA Cl- Cl- Cl- Cl- Cl- Cl- GABA PO4 In POSTSYNAPTIC MODULATION

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

b-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 b-adrenergic activation of postsynaptic cell takes place… Active during memory formation NE Glu Stabilization of LTP cAMP PKA Inhibition of protein phosphatase I

b-adrenergic receptor activation helps memories better memories when you are paying attention because of higher emotional stimulation

SEROTONIN 5-HT

PRESYNAPTIC MODULATION

See: Chapter 63. Cellular mechanisms of learning. Page 1247. “Principles of Neuroscience” Kandel ER et al 4th edition, 2000, McGraw-Hill See also, Chapter 13, Figure 13-12 in Kandel et al Or Chpater 50. Learning and memory: basic mechanisms. Page 1275 Fundamental Neuroscience, second edition, Squire LR et al, 2003, Academic Press

Humans Serotonin - a chemical manifestation of personality High level of serotonin: compulsives obsessive-compulsive disorders e.g. compulsive hand-washing Low levels of serotonin: depression, suicide. Listening to Prozac, P.D. Kramer, 1993

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 Re-uptake of 5-HT/serotonin

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 control Dopamine is the brain’s motivational chemical. It works on glutamate synapses to modulate their excitability. A shortage of brain dopamine causes an indecisive personality, unable to initiate even the body’s own movement. 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.

L-DOPA rescues Parkinsonian rabbits Rabbits treated with reserpine The same rabbits 15 minutes after treatment with L-DOPA Carlsson, 1960 See Science, vol 294, p1002, 2 November 2001

DARP-32 Dopamine and cAMP-regulated phosphoprotein Molecular weight, 32 kDa DARP-32 is a molecular integrator

Overlapping cell Neocortex neurons Neural ensembles

neocortex Substantia nigra Dop

1 2 3 4 Dop

1 3 4 2 Dop

neocortex Dop Substantia nigra

neocortex Substantia nigra Parkinson’s disease. No dopamine No neural ensembles can be selected

Schizophrenia? Active neural ensembles too extended? neocortex DA Substantia nigra

Other neuromodulators (NE, serotonin) probably work in a similar way to dopamine They assist with the selection/maintenance of different neural ensembles.

Molecular actions of dopamine

Polymorphisms of genes involved in aminergic (dopamine/serotonin) neurotransmission Effects on personality? Dopamine D4 receptor - novelty seeking Promoter of serotonin transporter gene - harm avoidance/anxiety

D4 dopamine receptor 16 amino acid repeat sequence present in two to 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 to life 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