Sketch the structure of a chemical synapse. Indicate relevant length scales.
What is meant by quantal release of neurotransmitter?
A vesicle in a pre-synaptic bouton will either release its entire neurotransmitter load, or none of it. Per vesicle neurotransmitter release is therefore binary.
What is the dependence of neurotransmitter release upon calcium?
- Higher voltage (from AP) opens Ca+ channels, causes Ca+ inflow
- The calcium binds with synaptotagmin
- This allows primed vesicles (those already half bound to plasma membrane) to fuse fully
- This release machinery happens through the SNARE complex on the presynaptic membrane
What are the scales of the synapse, synaptic cleft, vesicles
<1um
50nm
40nm
How do electrical synapses work?
AP can jump dendrites’ gap junctions if the dendrites are close enough.
What are electrograde signals?
Postsynaptic neurons can send back NTs, which may be important for regulation. These NTs can even be released from dendritic spines (not boutons).
What are the two types of vesicle refilling
‘Recycling’ may occur by either ‘kiss and run’ (vesicle returns to middle of bouton to be refulled) or ‘kiss and stay’ (vesicles remains at membrane and is just refilled there)
Sketch/Explain the vesicle refilling process
- H+ proteins pumped back into vesicle by V-type ATPase.
- The +ve internal charge of vesicles prompts nearby vesicular neurotransmitter transporters to retrieve NTs for it
How to increase the ~10% of vesicle NT release?
- More Ca+ (Hill coefficient = 4)
- Slower K+ channel repolarisation => slower AP => more chance for Ca2+ entering
- Bigger/better/more vesicles/SNARE Complex
How does short-term facilitation work?
Over a 100s millisecond period. An AP closely following the previous AP will result in a larger concentration of intracellular [Ca2+], thus increasing the likelihood of vesicle NT release (huge because of Hill coefficient = 4) and so larger EPSP.
How does short-term depression work?
Over a 100s millisecond period. An AP closely following the previous AP will result in less ‘primed’ vesicles (no time to replenish) so a lesser AP.
Explain post-tenatic potentiation
PTP is a high frequency firing of APs
=> activate protein kinase C (PKC)
=> phosphorylises Munc-18
=> is part of SNARE, so increases NT release rate
over a minutes timeframe
Explain presynaptic long-term potentiation
PTP increases Calcium amount
=> activates the Ca+ dependent enzyme adenylate
=> catalyses the conversion of ATP to cAMP
=> activates kinase A
=> phosphorylates synaptotagmin (a different synaptotagmin to the one involved in Ca / vesicle release)
=> causes long-term (hours) enhancement of NT release.
What is a metabotropic neurotransmitter receptor?
- One which is indirectly activated by sometimes-diffused NTs neurotransmitters such as GABA and glutamate.
- NT is coupled to a GTP-binding (G) protein. The binding of the neurotransmitter onto the receptor will activate the G protein leading to a
cascade of intracellular signaling that can modulate ionic channels or enzyme activity, or modify gene expression.
Describe one mechanism of presynaptic inhibition (via metabotropic receptors) and how it affects shortterm presynaptic plasticity
When G (from metabotropic receptors) inhibits calcium influx channels or SNARE complex. This can result in facilitative presynaptic dynamic for once that inhibitor is gone.
Describe how metabotropic receptors can neuromodulate post-synaptically
When G (from metabotropic receptors) opens the inhibitory GIRK channels. GIRK channels lead to inflow of K+, which hyperpolarises the potential, which makes the activation threshold less achievable. This effect is on the 0.5sec timescale, much slower than the ionotropic receptors
How is short term plasticity measured scientifically?
In neurophysiology short-term plasticity is often measured using paired-pulse protocol to assess the
release probability
Ionotropic vs metabotropic receptors
Ionotropic receptors are ligand-gated ion channels. They consist of multiple subunits that form a channel in the membrane. When the appropriate neurotransmitter binds to the receptor, it directly opens the ion channel, allowing ions to flow into or out of the cell. (AMPA, NMDA, GABA.A)
Metabotropic receptors are G-protein-coupled receptors (GPCRs). They do not directly form an ion channel. Instead, when a neurotransmitter binds to the receptor, it activates a G-protein inside the cell, which in turn triggers a cascade of intracellular signaling events. (GABA.B)
