Transcript Wisden_Zellbiol_IV_2 - uni

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
OUT
Cl-
Na+
Cl-
Na+
GABAA receptor
Inhibition
IN
Glutamate/AMPA
receptor
Excitation
Simple circuits
Feed-forward inhibition
Negative feedback
Feedback inhibition
Neocortex
Interneuron - uses GABA
Pyramidal neuron
- uses glutamate
Cerebral cortex
Sensory input
Information integration
cognition, thought,
mood, emotion
acetylcholine norepinephrine
serotonin
dopamine
Motor output
histamine
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.
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
Slow
Ion flow in/out
Second messenger cascades
milliseconds
seconds
1/1000 of a second !
Out
NH2
7 transmembrane
domain receptor
In
2nd messengers
COOH
G
Ionotropic
Metabotropic
The monoamines
Dopamine
Epinephrine (adrenergic)
Norepinephrine (noradrenergic)
Serotonin
Neurotransmitter
receptors
Neurotransmitter
receptors
Ion pumps
Second messengers
Protein kinases
Ion channels
Transcription Factors
Cell nucleus
7-transmembrane-domain receptors
Excitatory input
Glutamate
Neuromodulatory
inputs
NE
GluR
b1
DA
Neuromodulatory
inputs
ACh
D1
cAMP
M1
Ca2+
Ca2+-dependent
Kinases/phosphatases
PKC
Hist
PKA
H2
5-HT
IP3 + DG
5-HT2C
Down-stream substrates
Gene expression
Short-term synaptic modification
Hist
H1
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.
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
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)
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
Cocaine blocks the NET Stimulant
Reuptake of NE
NE potentiation of responses to GABA
Purkinje cells
Out
GABA
ClGABA
Cl-
PO4
Cl-
In
Cl- Cl- Cl- Cl- Cl-
GABA + cAMP
GABA + NE
GABA
response
GABA
time
Noradrenergic potentiation of cerebellar Purkinje cell responses
to GABA: cAMP as intracellular intermediary.
NE
b-adrenergic
receptor
GABAA receptor
b1
Gs
PO4
AC
cAMP
PKA reg
ATP
PKA cat
Out
GABA
ClGABA
Cl-
PO4
Cl-
In
Cl- Cl- Cl- Cl- Cl-
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…
NE
Active during memory
formation
Glu
Stabilization of LTP
PKA
Inhibition of
protein phosphatase I
cAMP
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
Fluoxetine/Prozac blocks the SERT
Treatment of depression.
anxiety disorders,
Re-uptake of 5-HT/serotonin
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 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
A. 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
Dop
Substantia
nigra
1
2
3
4
Dop
1
3
4
2
Dop
neocortex
Dop
Substantia
nigra
neocortex
Parkinson’s disease. No dopamine
No neural ensembles can be selected
Substantia
nigra
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
[email protected]
[email protected]
Alan Summerfield