Neuromodulation

“Classical” Synaptic Transmission • discrete structural entity

Action potential

• functionally discrete in space and time

Ca2+

Ca2+

Enzyme or fast reuptake Ligand-gated receptor

Synaptic cleft Na+

NEUROMODULATION IN THE CNS “setting” the activity level of neural pathways Longer term changes in: • neuronal membrane properties - e.g. excitability, response to synaptic input • synaptic strength: plasticity of synapses underlying behavioural changes - e.g. learning and memory

NEUROMODULATION IN THE CNS “setting” the activity level of neural pathway Behaviour • arousal – eg. sleep, appetite, locomotory activity; raised/lowered thresholds • learning and memory – alterations in the effectiveness of specific transmission pathways

“Classical” Synaptic Transmission •Fast - for rapid signal transmission •Short-lived (msec) •Ligand-gated (ionotropic) ion channels

e.g. ACh on skeletal muscle excitation

Local Neuromodulation •Slower •Longer-lived (sec) •Metabotropic receptors

e.g. ACh on cardiac muscle – slows heart rate

Extrasynaptic (“ectopic”) Neuromodulation •Slow •Long-lived (min) •Metabotropic receptors

e.g. oxytocin and vasopressin on brain pathways – altered reproductive and sexual behaviour

Two types of neurotransmitter receptors Transmitter-gated ion channels

G-protein coupled receptors

“ionotropic”

“metabotropic”

e.g.

e.g.

•Nicotinic ACh receptor (Na+/K+)

•Muscarinic ACh receptor (K+)

•GABAA receptor (Cl-)

•Serotonin 5HT receptor (cAMP)

Postsynaptic response a few ms

Postsynaptic response 100 ms to minutes (or even longer)

G-Protein-coupled receptors Guanosine triphosphate (GTP)-binding protein

A

neurotransmitter

receptor

ion channel

e.g. Muscarinic ACh receptor (K+ channel)

G-protein

B enzyme

Second messenger cascade

e.g.Serotonin 5HT receptor (cAMP)

Receptor modulation

Protein phosphorylation → other cell processes

Second messenger pathways G-Protein Adenylyl cyclase

Phospholipase C

Cyclic AMP

Inositol trisphosphate IP3

Diacylglycerol DAG

Protein kinase A PKA

Ca2+ release from stores

Protein kinase C PKC

NEUROMODULATION: electrical activity, enzyme activity, gene expression

•CASCADE - allows for amplification of signal at different points in the cascade •TIME COURSE of response is determined by enzyme kinetics •Can produce LONG TERM changes in neuronal function via gene expression

Short to long duration changes in neuronal properties – “plasticity” (Co-localisation of ‘classical’ neurotransmitter and neuromodulator)

Neurotransmitters that may also act as neuromodulators •Acetylcholine – muscarinic receptors (K+ channels) •GABA – GABAB receptor (K+ channels) •Serotonin (5HT) (↑cAMP) •Noradrenaline - β receptor (↑cAMP) •Noradrenaline - α 2 receptor (↓cAMP) •Glutamate – metabotropic glutamate receptors (↓cAMP or ↑PKC) •Dopamine •Enkephalin NB: It is the receptor that determines the type of postsynaptic response

An example of short term neuromodulation Mammalian hippocampal neurons – noradrenaline increases excitability Noradrenaline or cAMP Noradrenaline → cAMP → closes K+ channels in postsynaptic membrane

mV

ms

Glutamate (ionotropic via Ca2+ channels)

An example of ‘postsynaptic neuromodulation’

post pre

K+

Presynaptic inhibition and facilitation Selective regulation of synaptic efficacy Change in effectiveness/efficacy of synapse

Neurotransmitter Neuromodulator

Presynaptic Inhibition

GABA reduces synaptic transmission at a specific synapse

Presynaptic Facilitation

An example of short/long term neuromodulation – “presynaptic facilitation” Increased neurotransmitter release from Aplysia sensory neurons - underlies associative learning 5-HT

cAMP responsive elements CRE cAMP inducible genes

cAMP Ubiquitin Persistent PKA hydrolase kinase closes

Voltage-gated K channels