Circuit-specific control of the medial entorhinal inputs to the dentate gyrus by atypical presynaptic NMDARs activated by astrocytes

Abstract

Here, we investigated the properties of presynaptic N-methyl-d-aspartate receptors (pre-NMDARs) at corticohippocampal excitatory connections between perforant path (PP) afferents and dentate granule cells (GCs), a circuit involved in memory encoding and centrally affected in Alzheimer’s disease and temporal lobe epilepsy. These receptors were previously reported to increase PP release probability in response to gliotransmitters released from astrocytes. Their activation occurred even under conditions of elevated Mg2+ and lack of action potential firing in the axons, although how this could be accomplished was unclear. We now report that these pre-NMDARs contain the GluN3a subunit conferring them low Mg2+ sensitivity. GluN3a-containing NMDARs at PP-GC synapses are preponderantly presynaptic vs. postsynaptic and persist beyond the developmental period. Moreover, they are expressed selectively at medial—not lateral—PP axons and act to functionally enhance release probability specifically of the medial perforant path (MPP) input to GC dendrites. By controlling release probability, GluN3a-containing pre-NMDARs also control the dynamic range for long-term potentiation (LTP) at MPP-GC synapses, an effect requiring Ca2+ signaling in astrocytes. Consistent with the functional observations, GluN3a subunits in MPP terminals are localized at sites away from the presynaptic release sites, often facing astrocytes, in line with a primary role for astrocytic inputs in their activation. Overall, GluN3A-containing pre-NMDARs emerge as atypical modulators of dendritic computations in the MPP-GC memory circuit.

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development

“…Nevertheless, our findings make it clear that there is a maturation-associated shift from the involvement of NMDARs to mGluRs in hippocampal plasticity. Forms of preLTP that are dependent on preNMDARs have been described in the hippocampus 41 and at entorhinal cortex to DG synapses [48][49][50][51] and preLTP forms independent of NMDARs have also been described at hippocampal MF-CA3 synapses 52 , in the cerebellum 53 , thalamus 54 , subiculum 55 , amygdala 56 , and neocortex 57 . The requirement of mGluRs for some forms of preLTP has previously been defined in the hippocampus 45,47 , although these preLTPs were not induced using STDP protocols.…”

Presynaptic NMDARs and astrocytes ally to control circuit-specific information flow

“…Preembedding immunogold analysis lends key experimental support. While previous work found GluN3a-NMDARs at postsynaptic and extrasynaptic plasma membranes (5), Savtchouk et al (3) observed that on MPP axons, the majority of GluN3a immunogold particles are presynaptic. GluN3a particles were located away from the synaptic cleft, closely apposed to astrocytic membranes, and were virtually absent from LPP axons.…”

“…As mentioned, one commonality of pre-NMDARs is their strategic location at subsets of synapses to control the induction of time-restricted or circuit-specific forms of short-or long-term plasticity. Expanding on this literature, Savtchouk et al (3) report that LTP is enhanced at GluN3a-null MPP-GC synapses and suggest that GluN3a-pre-NMDARs impose a basal "prepotentiation" state that narrows the dynamic range for LTP induction. Blocking Ca 2+ elevation in astrocytes by loading the Ca 2+ chelator 1,2-Bis(2-aminophenoxy)ethane N,N,N′,N′-tetraacetic acid (BAPTA) recapitulated the enhanced LTP, suggesting a role for pre-NMDAR-astrocyte coupling in this modulation.…”

“…The current work (3) demonstrates that this is possible because of the additional presence in the receptor channel of the atypical GluN3a subunit, which largely relieves NMDAR dependence on Mg 2+ block (5). Combining patch-clamp electrophysiology and high-resolution immunogold electron microscopy in wild-type and GluN3a knockout (KO) mice, Savtchouk et al (3) report that the observed increase in glutamate release probability is circuit specific and occurs at MPP (but not LPP) fibers due to an anatomical difference: the selective expression of pre-NMDARs containing GluN3a subunits (GluN3a-pre-NMDARs) at MPP axons contacting GCs. Beautiful electron microscopy images show how GluN3a-pre-NMDARs are located in presynaptic terminals, away from synaptic clefts, and often face astrocytic membranes.…”

“…Of these, GluN2c, GluN2d, or GluN3a lower the sensitivity to Mg 2+ block of the channel and have been reported to incorporate into pre-NMDARs in other brain areas (12,13). Using GluN3a KO mice, Savtchouk et al (3) found that local puffs of NMDA did not affect mEPSC frequency, as seen in control mice. The PPR was increased at MPP-GC (but not LPP-GC) KO synapses, possibly reflecting a lower probability of release due to lack of pre-NMDARs containing GluN3a, and ifenprodil effects were occluded.…”