Central synapses (neuromodulation and plasticity)

define neuromodulation

the spillover effects of neurotransmitters which simultaneously modulate synaptic function and/or cellular exctitability across volumes of tissue and exert slow modulatory effects largely via activation of G protein couple receptors

What do diffuse modulatory systems regulate?

attention, learning and moood and targets of many psychoactive drugs

What does neuromodulation occur predominately through?

non synaptic activation of metabotropic receptors

What are two types of neuromodulation?

optogenetics and TMS

What are the 4 main neurotransmitter systems used for long range and diffuse modulation of brain state?

acetylcholine, serotonin, noradrenaline, dopamine

What are the hubs for acetylcholine?

• basal forebrain - cortical projecting cholinergic neurons

• dorsolateral pontine tegmental area - brain stem cholinergic neurons

Experiment for acetylcholine?

Pinot et al (2013)

• mice to show that activating cholinergic basal forebrain neurons leads to desynchronisation of activity in PVC consistent with increased cortical arousal

What does serotonin affect and where are neurons located?

• mood

• raphe nuclei (projects dorsal to cortex or south)

Experiment with serotonin?

What does noradrenaline regulate and where sourced?

• arousal and sleep to wake

• neurons in locus coeruleus

Experiment for noradrenaline?

Carter et al (2010)

• optical stimulation long term increased locomotor activity

• optical stimulation during sleep led to brief sleep to wake transitions

What are the 4 main dopaminergic pathways and what do they control?

• mesolimbic system

  • reward/motivation

• mesocortical pathway

  • cognition/emotion

• nigrostriatal from substantia nigra

  • movement

• tuberoinfindibular from hypothalamus

  • hormone regulation

Experiment for dopamine?

What is neuromodulation largely mediated by?

metabotropic receptors which activate intracellular transduction pathways via G proteins

What can metabotropic receptors do?

indirectly open or close ion channels via a second messenger cascade

What does signalling via second messenger cascades enable?

amplification

What are the 3 principle targets for modulation of neuronal function?

• presynaptic release

  • modulate ion channels and AP induced Ca influx

  • tends to decrease evoked release

• postsynaptic response

  • GPCRs can modulate ligand gated ion channels altering reponse to vesicular release

• neuronal excitability

  • regulate membrane polarisation

Define synaptic plasticity?

activity dependent changes in synaptic strength that outlast the direct effects of neurotransmitter release, thought to be important for behavioural learning and memory

Define long term potentiation?

• process by which synaptic connections between neurons become stronger with frequent activation

• way in which brain changes in response to experience

Who discovered long term potentiation?

Bliss and Lomo

• it operates at many glutamatergic synapses

• hihgloghts the functional importance of receptor diversity eg AMPA/kainate vs NMDA

Outline NMDA-receptor dependent LTP?

• glutamate release activates AMPA receptor

• NMDA receptor not activated because ion channel blocked by magnesium ion

• frequent APs cause greater stimulation of AMPA receptors causes postsynaptic neuron to depolarise

• this causes voltage dependent mg blockage of NMDA receptor to be removed allowing Ca ions to flow through

• influx of Ca initiates cellular mechanism that causes more AMPA receptors to be inserted in neurons membrane

  • new are also more responsive to glutamate so allow more positively charged ions to enter cell when activated

• post synaptic cell now more sensitive to glutamate because has more receptors

• also potentially singals that travel back across synapse to initiate greater levels of glutamate release

• synapse stronger and more likely to be activated

Morris water maze experiment?

• rats injected with NMDA antagonist

• control rats learn to remember where submerged platform is, others do not

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