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

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

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

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

3 OUT IN Cl - Na + GABA A receptorGlutamate/AMPA receptor GABAGABA G lu Inhibition Excitation

4 Simple circuits

5 Feed-forward inhibition

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7 Negative feedback Feedback inhibition

8 Neocortex Interneuron - uses GABA Pyramidal neuron - uses glutamate

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

10 Arousal: 1.Processing signals relate to plain & pleasure. Regulating body homeostasis 2.Emotion and feeling 3.Attention 4.Wakefulness & sleep 5.learning The construction of consciousness.

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

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

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14 Out In G 7 transmembrane domain receptor 2nd messengers NH 2 COOH

15 Ionotropic Metabotropic

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

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

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19 7-transmembrane-domain receptors

20 Glutamate Ca 2+ Ca 2+ -dependent Kinases/phosphatases Down-stream substrates Gene expression Short-term synaptic modification Long-term synaptic modification cAMP PKA Hist DA NE ACh 5-HT Hist PKC IP3 + DG GluR 11 D1D1 H2H2 M1M1 5-HT 2C H1H1 Excitatory input Neuromodulatory inputs Neuromodulatory inputs

21 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.

22 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

23 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)

24 Carlsson, A (2001). A paradigm shift in brain research. Science, vol. 294, p **Greengard, P (2001). The neurobiology of slow synaptic transmission. Science, vol. 294, p **Kandel, ER (2001). The molecular biology of memory storage: a dialogue between genes and synapses. Science, vol. 294, p

25 Catecholamines Norephinephrine

26 A synapse that uses norepinephrine (NE)

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

28 NE potentiation of responses to GABA Purkinje cells

29 PO 4 Cl - GABA Cl - Cl - Cl - Cl - Cl - Cl - GABA Out In

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

31 11 NE Gs AC ATP cAMP PKA reg PKA cat PO 4 GABA A receptor  -adrenergic receptor

32 PO 4 Cl - GABA Cl - Cl - Cl - Cl - Cl - Cl - GABA Out In POSTSYNAPTIC MODULATION

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

34  -adrenergics and memory PresynapticPostsynaptic Before LTP After LTP More glutamate receptors = bigger response

35 After LTP More glutamate receptors = bigger response After several hours……. PresynapticPostsynaptic LTP decays

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

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

38 SEROTONIN 5-HT

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41 PRESYNAPTIC MODULATION

42 See: Chapter 63. Cellular mechanisms of learning. Page “Principles of Neuroscience” Kandel ER et al 4th edition, 2000, McGraw-Hill See also, Chapter 13, Figure 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

43 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 Humans

44 The 5-HT neurons in the brain

45 A synapse that uses serotonin/5-HT

46 Re-uptake of 5-HT/serotonin Fluoxetine/Prozac blocks the SERT Treatment of depression. anxiety disorders, obsessive-compulsive disorders

47 Genetic variation in the gene promoter region of the serotonin transporter. risk factor for anxiety, alcoholism, mood disorders slight differences in level of expression

48 Catecholamines Dopamine

49 Dopamine pathways in the brain

50 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.

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

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

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56 Overlapping cell Neural ensembles Neocortex neurons

57 Dop neocortex Substantia nigra

58 Dop

59 4 2 13

60 neocortex Substantia nigra

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

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

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

64 Molecular actions of dopamine

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67 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

68 D4 dopamine receptor 16 amino acid repeat sequence present in two to 11 copies - minisatellite phrase

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

70 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!

71 Neuromodulators Slow synaptic transmission Alan Summerfield


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