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“Classical” Synaptic Transmission

• discrete structural
entity
• functionally discrete Action
in space and time potential

Ca2+ Ca2+

Enzyme or
fast re-
uptake
Synaptic
Ligand-gated
cleft
receptor
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
e.g. ACh on
•Short-lived (msec) skeletal muscle -
excitation
•Ligand-gated (ionotropic) ion channels

Local Neuromodulation
•Slower
e.g. ACh on
•Longer-lived (sec) cardiac muscle –
slows heart rate
•Metabotropic receptors

Extrasynaptic (“ectopic”) Neuromodulation
•Slow e.g. oxytocin and
•Long-lived (min) vasopressin on brain
pathways – altered
•Metabotropic receptors 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 Postsynaptic response 100 ms
ms to minutes (or even longer)
G-Protein-coupled receptors
Guanosine triphosphate (GTP)-binding protein

neurotransmitter ion channel
A e.g. Muscarinic
ACh receptor
receptor (K+ channel)
G-protein

B e.g.Serotonin 5HT
receptor (cAMP)
enzyme Receptor modulation

Protein
Second messenger cascade phosphorylation →
other cell processes
Second messenger pathways

G-Protein

Adenylyl cyclase Phospholipase C

Cyclic AMP Inositol trisphosphate Diacylglycerol
IP3 DAG

Protein kinase A Ca2+ release from Protein kinase C
PKA stores 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
post
Glutamate (ionotropic
via Ca2+ channels) pre
K+
An example of
‘postsynaptic
neuromodulation’
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 cAMP
elements CRE

Ubiquitin Persistent PKA
cAMP inducible
hydrolase kinase
genes closes

Voltage-gated
K channels