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. Inhibition Excitation OUT Cl- Na+ Cl- Na+ IN GABA Glu 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 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

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. Transcription Factors
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 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

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. 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

23. 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)

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 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. Out
Cl-
GABA
Cl-
Cl- Cl- Cl- Cl- Cl-
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. NE
GABAA receptor
b-adrenergic
receptor AC
PO4 Gs
cAMP
PKA reg
PKA cat
ATP

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

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

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

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

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 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. 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

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. 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

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

56. Overlapping cell
Neocortex
neurons
Neural ensembles

57. neocortex
Substantia
nigra
Dop

58. 1 2 3 4
Dop

59. 1 3 4 2
Dop

60. neocortex
Dop
Substantia
nigra

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

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

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

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