GluN2B-Containing NMDA Receptors Promote Glutamate Synapse Development in Hippocampal Interneurons

Abstract

In postnatal development, GluN2B-containing NMDARs are critical for the functional maturation of glutamatergic synapses. GluN2B-containing NMDARs prevail until the second postnatal week when GluN2A subunits are progressively added, conferring mature properties to NMDARs. In cortical principal neurons, deletion of GluN2B results in an increase in functional AMPAR synapses, suggesting that GluN2B-containing NMDARs set a brake on glutamate synapse maturation. The function of GluN2B in the maturation of glutamatergic inputs to cortical interneurons is not known. To examine the function of GluN2B in interneurons, we generated mutant mice with conditional deletion of GluN2B in interneurons (GluN2B ⌬GAD67). In GluN2B ⌬GAD67 mice interneurons distributed normally in cortical brain regions. After the second postnatal week, GluN2B ⌬GAD67 mice developed hippocampal seizures and died shortly thereafter. Before the onset of seizures, GluN2B-deficient hippocampal interneurons received fewer glutamatergic synaptic inputs than littermate controls, indicating that GluN2B-containing NMDARs positively regulate the maturation of glutamatergic input synapses in interneurons. These findings suggest that GluN2B-containing NMDARs keep the circuit activity under control by promoting the maturation of excitatory synapses in interneurons.

Diverse roles for ionotropic glutamate receptors on inhibitory interneurons in developing and adult brain

“…A and B ; Table ) (Kelsch et al . ). This decreased excitatory drive promoted hippocampal seizures and subsequent lethality (Table ) (Kelsch et al .…”

“…This decreased excitatory drive promoted hippocampal seizures and subsequent lethality (Table ) (Kelsch et al . ). Selective ablation of NMDARs later in development in PV‐positive interneurons alters theta and gamma oscillations indicating a critical role for NMDARs in PV–interneuron‐mediated circuit entrainment (Table ) (Korotkova et al .…”

“…A and B are reproduced with permission from Kelsch et al . (). C–G are reproduced with permission from De Marco Garcia et al .…”

“…PV‐positive interneurons) physiological roles have been described at cellular (Lei & McBain, ; Kelsch et al . , ; Matta et al . ), network (Korotkova et al .…”

NMDAR-mediated transcriptional control of gene expression during the development of medial ganglionic eminence-derived interneurons

“…This becomes particularly important as the developing brain contains higher ambient glutamate levels than the adult brain [16]. Collectively, higher ambient glutamate, developmental expression of iGluRs and recruitment of glutamatergic signaling is considered to be trophic [8, 17, 18] and thought to engage mechanisms to regulate various aspects of interneuron development including morphological and electrical maturation to promote appropriate circuit integration [9, 11, 14, 16, 19–22].…”