See: Chapter 13. Modulation of synaptic transmission: Second messengers.

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

4. Simple circuits

5. Feed-forward inhibition

7. Negative feedback Feedback inhibition

8. Neocortex Interneuron - uses GABA Pyramidal neuron - uses glutamate

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

10. Arousal: • Processing signals relate to plain & pleasure. Regulating • body homeostasis • Emotion and feeling • Attention • 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 !

14. 7 transmembrane domain receptor Out NH2 In 2nd messengers G COOH

15. Ionotropic Metabotropic

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

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

19. 7-transmembrane-domain receptors

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

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, 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

25. Catecholamines Norephinephrine

26. A synapse that uses norepinephrine (NE)

27. 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

28. NE potentiation of responses to GABA Purkinje cells

29. Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Out GABA GABA PO4 In

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

31. PKA reg PKA cat NE GABAA receptor b-adrenergic receptor b1 AC PO4 Gs cAMP ATP

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

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

34. Before LTP Presynaptic Postsynaptic After LTP More glutamate receptors = bigger response b-adrenergics and memory

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

36. 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

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

38. SEROTONIN 5-HT

41. PRESYNAPTIC MODULATION

42. 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

43. 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

44. The 5-HT neurons in the brain

45. A synapse that uses serotonin/5-HT

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

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.