CSB332H1 Lecture Notes - Lecture 12: Nmda Receptor, Ampa Receptor, Synaptic Plasticity
14 May 2018
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Lecture 12(a): Altering Synapses II
Synapses in the Brain:
• Majority of the synapses (80%) found in the brain are glutamatergic; therefore looking at
synapses releasing glutamate and glutamate receptors
o Glutamate receptors include: AMPARs, NMDARs and Kainate receptors
• Majority of all synaptic plasticity that involve glutamatergic synapses consist of NMDA
receptors and AMPA receptors
o NMDA is crucial and critical – acts as a coincidence detector allowing changes to
occur in the post-synaptic cells
Synaptic Maturation:
• During early development (before we are born) majority
of the synapses are silent synapses – only contain
NMDA receptors, no AMPA receptors present
o When glutamate is binding to NMDA receptors,
they are incapable of opening
§ NMDA receptors are blocked at rest via Mg2+ and cannot respond until the
membrane is depolarized to remove the occluding Mg2+
• After birth, during maturation, those silent synapses become functional synapses –
movement of AMPA receptors are directed to areas of silent synapses
o When glutamate binds to AMPA receptors, influx of Na+ occurs, depolarizing the
membrane which allows NMDA receptors to open to allow:
§ Influx of Na+ => further depolarizing the membrane
§ Influx of Ca2+ => allow for synaptic plasticity to occur
ð AMPA receptors are required for depolarization | NMDA receptors are required for plasticity
Mechanism of Long Term Potentiation (LTP):
• NMDA receptor is the most important mediator for long-term potentiation
o 98% of all synaptic plasticity involving glutamate receptors are NMDAR dependent
§ NMDAR is the only glutamatergic receptor allowing for Ca2+ influx
Pathway:
• When the membrane is depolarized & glutamate is present
NMDAR allow for the influx of Ca2+ activating CaM
• CaM activates CaMKII which then autophosphorylates
(CaM does not phosphorylate CaMKII, CaM allows CaMKII
to autophosphorylate itself)
ð Phosphorylated CaMKII generates LTP via:
o Intracellular AMPAR are trafficked to the cell surface –
!
glutamate response
o AMPAR already on cell surface are phosphorylated –
!
conductance (open longer)
§ Both mechanisms function to further depolarize the membrane for the same
amount of glutamate released post-synaptically
Signal remains
after the
synaptic input ends
LTP = insertion & phosphorylation of AMPARs on cell membrane
Document Summary
Synaptic maturation: during early development (before we are born) majority of the synapses are silent synapses only contain. Nmda receptors, no ampa receptors present: when glutamate is binding to nmda receptors, they are incapable of opening. Influx of na+ => further depolarizing the membrane. Influx of ca2+ => allow for synaptic plasticity to occur. Ampa receptors are required for depolarization | nmda receptors are required for plasticity. Mechanism of long term potentiation (ltp): nmda receptor is the most important mediator for long-term potentiation, 98% of all synaptic plasticity involving glutamate receptors are nmdar dependent. Nmdar is the only glutamatergic receptor allowing for ca2+ influx. Nmdar allow for the influx of ca2+ activating cam: cam activates camkii which then autophosphorylates (cam does not phosphorylate camkii, cam allows camkii to autophosphorylate itself) Phosphorylated camkii generates ltp via: intracellular ampar are trafficked to the cell surface glutamate response, ampar already on cell surface are phosphorylated conductance (open longer)
