Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors

Abstract

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT.

Neuronal Ca2+ signalling at rest and during spontaneous neurotransmission

“…; Abrahamsson et al . ). Interestingly, this regulation may not depend on canonical NMDA receptor subunits and may not require Ca 2+ influx through the NMDA receptor (Abrahamsson et al .…”

“…Interestingly, this regulation may not depend on canonical NMDA receptor subunits and may not require Ca 2+ influx through the NMDA receptor (Abrahamsson et al . ). This form of presynaptic NMDA receptor regulation possibly depends on the recently identified metabotropic function of NMDARs to promote resting neurotransmission (Abrahamsson et al .…”

“…This form of presynaptic NMDA receptor regulation possibly depends on the recently identified metabotropic function of NMDARs to promote resting neurotransmission (Abrahamsson et al . ).…”

Increased presynaptic excitability in a migraine with aura mutation

“…Recent evidence suggests that RRP replenishment may be modulated by presynaptic NMDA receptors at cortical synapses 31 . CK1 isoforms phosphorylate NMDA receptors, especially NR2B subunits found presynaptically in adult cortex, decreasing their conductance 26 .…”

“…Presynaptic NMDA receptors have been shown to specifically mediate evoked release 31 and are implicated in regulating vesicle replenishment at different cortical synapses, either through Ca +2 /calmodulin dependent or several other downstream molecular mechanisms 31,56–58 . NMDA receptors are a known substrate for CK1 family of kinases, most prominently affecting NR2B subunit containing receptors 26 .…”