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:
See: Chapter 13. Modulation of synaptic transmission: Second messengers. “Principles of Neuroscience” Kandel ER et al 4th edition, 2000, McGraw-Hill Page 229
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
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 Ion flow in/out milliseconds Slow Second messenger cascades seconds 1/1000 of a second !
Out In G 7 transmembrane domain receptor 2nd messengers NH 2 COOH
The monoamines Dopamine Epinephrine (adrenergic) Norepinephrine (noradrenergic) Serotonin
Second messengers Protein kinases Transcription Factors Cell nucleus Ion pumps Ion channels Neurotransmitter receptors Neurotransmitter receptors
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 11 D1D1 H2H2 M1M1 5-HT 2C H1H1 Excitatory input Neuromodulatory inputs Neuromodulatory inputs
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, 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
A synapse that uses norepinephrine (NE)
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
NE potentiation of responses to GABA Purkinje cells
PO 4 Cl - GABA Cl - Cl - Cl - Cl - Cl - Cl - GABA Out In
time GABA response GABA GABA + NE GABA + cAMP Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cAMP as intracellular intermediary.
11 NE Gs AC ATP cAMP PKA reg PKA cat PO 4 GABA A receptor -adrenergic receptor
PO 4 Cl - GABA Cl - Cl - Cl - Cl - Cl - Cl - GABA Out In POSTSYNAPTIC MODULATION
Why does a small amount of stress help you learn better?
-adrenergics and memory PresynapticPostsynaptic Before LTP After LTP More glutamate receptors = bigger response
After LTP More glutamate receptors = bigger response After several hours……. PresynapticPostsynaptic LTP decays
Unless -adrenergic activation of postsynaptic cell takes place… NE Glu cAMP PKA Inhibition of protein phosphatase I Active during memory formation Stabilization of LTP
-adrenergic receptor activation helps memories -better memories when you are paying attention because of higher emotional stimulation
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
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
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
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.
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
DARP-32 Dopamine and cAMP-regulated phosphoprotein Molecular weight, 32 kDa DARP-32 is a molecular integrator
neocortex Substantia nigra Parkinson’s disease. No dopamine No neural ensembles can be selected
DA neocortex Substantia nigra Schizophrenia? Active neural ensembles too extended?
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 Alan Summerfield