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Divergent Signalling of Presynaptic NMDA Receptors in Neocortical Circuits
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Divergent Signalling of Presynaptic NMDA Receptors in Neocortical Circuits
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Dissertation
Divergent Signalling of Presynaptic NMDA Receptors in Neocortical Circuits
2019
Overview
NMDA receptors (NMDARs) play a critical role in neuronal communication and are essential mediators of synaptic plasticity mechanisms within the central nervous system. In the traditional view, NMDARs act as coincidence detectors in Hebbian plasticity, fluxing calcium when simultaneously glutamate bound and depolarized to initiate signalling cascades which ultimately result in synaptic modification. Coincidence detection relies on NMDARs situated postsynaptically, yet NMDARs also exist presynaptically (preNMDARs) at select synapse-types, which suggests their contributions to synaptic plasticity and information processing may be distinct. Indeed, preNMDARs regulate the probability of neurotransmitter release, however the underlying molecular mechanisms remain largely unknown. Our lab has recently shown that in L5 pyramidal cells of mouse primary visual cortex, preNMDARs differentially regulate evoked and spontaneous neurotransmitter release through two presynaptic proteins: RIM1αβ and JNK2, respectively. Here I further explore this dichotomy. As preNMDAR-mediated induction of timing-dependent long-term depression (tLTD) has been shown to be independent of presynaptic firing frequency, I hypothesized that preNMDARs may further rely on JNK2 signalling to regulate tLTD in a similar manner as spontaneous release. Indeed, in patch recordings of L5 pyramidal cell pairs, tLTD was abolished upon JNK2 inhibition; however, tLTD in RIM1αβ knock out was indistinguishable from control. In sum, tLTD requires preNMDAR-mediated JNK2 signalling in a manner independent of RIM1αβ. This finding elucidates the criteria by which preNMDARs may select competing signalling pathways; preNMDARs appear to form a dual-pass filter, capable of regulating neurotransmitter release through independent mechanisms depending on presynaptic frequency requirements. As preNMDARs operate in a non-ionotropic manner during JNK-mediated regulation of spontaneous release, tLTD may similarly require this mode of unconventional NMDAR signalling
