see: chapter 13. modulation of synaptic transmission: second messengers. “principles of...
TRANSCRIPT
See:
Chapter 13. Modulation of synaptic transmission:Second messengers.
“Principles of Neuroscience” Kandel ER et al4th edition, 2000, McGraw-Hill
Page 229
Fast: GABA, glutamate, acetylcholine
Slow: biogenic aminesDopamineSerotonin/5-HTNEAcetylcholinePeptides
OUT
IN
Cl-
Cl-
Na+
Na+
GABAA receptor Glutamate/AMPAreceptor
GA
BA
Gl
u
Inhibition Excitation
Simple circuits
Feed-forward inhibition
Negative feedback
Feedback inhibition
Neocortex
Interneuron - uses GABA
Pyramidal neuron- uses glutamate
Information integrationcognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
acetylcholine norepinephrineserotonin dopamine histamine
Information integrationcognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
Arousal:
1. Processing signals relate to plain & pleasure. Regulatingbody homeostasis
4. Emotion and feeling5. Attention6. Wakefulness & sleep5. learning
The construction of consciousness.
Fast synaptic transmission -ligand-operated ion channelsthe hardware of the brain
Slow synaptic transmission: the software that controlsfast transmission
Ionotropic and metabotropic receptors
Fast
Ion flow in/out
milliseconds
Slow
Second messenger cascades
seconds
1/1000 of a second !
Out
In
G
7 transmembrane domain receptor
2nd messengers
NH2
COOH
Ionotropic
Metabotropic
The monoamines
Dopamine
Epinephrine (adrenergic)
Norepinephrine (noradrenergic)
Serotonin
Second messengers
Protein kinases
Transcription FactorsCell nucleus
Ion pumps
Ion channels
Neurotransmitterreceptors
Neurotransmitterreceptors
7-transmembrane-domain receptors
Glutamate
Ca2+
Ca2+-dependentKinases/phosphatases
Down-stream substrates
Gene expression
Short-term synaptic modification Long-term synaptic modification
cAMP
PKAHist
DA
NE ACh
5-HT
HistPKC
IP3 + DG
GluR
1
D1
H2
M1
5-HT2C
H1
Excitatory input
Neuromodulatory inputs
Neuromodulatory inputs
Particular modulator transmitters should not be regardedas purely excitatory or inhibitory.
Their exact action depends on context.
On the same cell, they can be either excitatory or inhibitorydepending on the state of the cell.
The Nobel prize in 2000 went to three neuroscientistsfor 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 neuroscientistsfor 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: adialogue between genes and synapses.Science, vol. 294, p1030-1038
Catecholamines
Norephinephrine
A synapse that uses norepinephrine (NE)
Reuptake of NE
Monoamine oxidase, located on outer membraneof mitochondria; deaminates catecholamines free innerve terminal that are not protected by vesicles
Selective inhibitor,reboxetine Cocaine blocks the NET
Antidepressant
MAO Inhibitors
Stimulant
NE potentiation of responses to GABA
Purkinje cells
PO4
Cl-
Cl-
GABACl-
Cl- Cl- Cl- Cl- Cl-
GABA
Out
In
time
GABAresponse
GABA
GABA + NE
GABA + cAMP
Noradrenergic potentiation of cerebellar Purkinje cell responsesto GABA: cAMP as intracellular intermediary.
1
NE
Gs AC
ATP
cAMP
PKA reg
PKA cat
PO4
GABAA receptor-adrenergicreceptor
PO4
Cl-
Cl-
GABACl-
Cl- Cl- Cl- Cl- Cl-
GABA
Out
In POSTSYNAPTIC MODULATION
Why does a small amount of stress help you learn better?
-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 -adrenergic activation of postsynaptic cell takes place…
NE
Glu
cAMPPKA
Inhibition ofprotein phosphatase I
Active during memoryformation
Stabilization of LTP
-adrenergic receptor activation helps memories
-better memories when you are paying attention because of higher emotional stimulation
SEROTONIN5-HT
PRESYNAPTICMODULATION
See:
Chapter 63. Cellular mechanisms of learning.Page 1247.“Principles of Neuroscience” Kandel ER et al4th edition, 2000, McGraw-Hill
See also, Chapter 13, Figure 13-12 in Kandel et al
Or
Chpater 50. Learning and memory: basic mechanisms.Page 1275Fundamental Neuroscience, second edition,Squire LR et al, 2003, Academic Press
Serotonin - a chemical manifestation of personality
High level of serotonin: compulsivesobsessive-compulsive disorderse.g. compulsive hand-washing
Low levels of serotonin: depression, suicide.
Listening to Prozac, P.D. Kramer, 1993
Humans
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
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 controlDopamine is the brain’s motivational chemical. It works onglutamate synapses to modulate their excitability.
A shortage of brain dopamine causes an indecisivepersonality, unable to initiate even the body’s ownmovement. 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.
Rabbits treated withreserpine
The same rabbits 15 minutes after treatment withL-DOPA
A. Carlsson, 1960See Science, vol 294, p1002, 2 November 2001
L-DOPA rescues Parkinsonian rabbits
DARP-32
Dopamine and cAMP-regulated phosphoproteinMolecular weight, 32 kDa
DARP-32 is a molecular integrator
Overlapping cell
Neural ensembles
Neocortexneurons
Dop
neocortex
Substantianigra
1
4
3
2
Dop
4
2
1 3
Dop
Dop
neocortex
Substantianigra
neocortex
Substantianigra
Parkinson’s disease. No dopamineNo neural ensembles can be selected
DA
neocortex
Substantianigra
Schizophrenia?Active neural ensembles too extended?
Other neuromodulators (NE, serotonin) probablywork in a similar way to dopamine
They assist with the selection/maintenance of differentneural ensembles.
Molecular actions of dopamine
Polymorphisms of genes involved in aminergic (dopamine/serotonin) neurotransmission
Effects on personality?
Dopamine D4 receptor - novelty seekingPromoter of serotonin transporter gene - harm avoidance/anxiety
D4 dopamine receptor
16 amino acid repeat sequence present in twoto 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 tolife 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
Alan Summerfield