Rationale:
According to the classical Hebbian learning model, postsynaptic NMDA receptors modulate the impact of neuronal signals by detecting coincident depolarization of the synaptic partners. However, recent evidence suggests that NMDA receptors are also expressed presynaptically in subsets of cortical synapses, thereby influencing synaptic communication via a wholly distinct mechanism. As NMDA receptors are involved in a wide range of normal functions ranging from development to plasticity and are considered high confidence therapeutic targets for both neurological disease and neuropsychiatric indications, a complete mechanistic understanding of these receptors is paramount. Glutamate- and glycine-activated NMDA receptors are tetrameric assemblies of two GluN1 and two GluN2 subunits, of which there are four types (GluN2A,B,C,D) that control channel properties and synaptic time course. Among the GluN2 subunits, GluN2D has unique properties (much slower kinetics, higher glutamate affinity) and is the least studied subtype.
Methods: We combined a novel mouse model showing GluN2D surface expression, 2-photon and superresolution microscopy, high-resolution patch clamp electrophysiology, and modeling, to evaluate the locus of GluN2D expression and function at PV interneuron synapses in the hippocampus.
Results:
Here we show multiple lines of evidence including that GluN2D-containing NMDA receptors are functionally localized at the presynaptic basket terminals of ‘fast-spiking’ parvalbumin (PV) interneurons in the mature hippocampus. Further, we examined putative mechanisms by which they are trafficked to presynaptic boutons in PV basket terminals. We show that the basal activity of GluN2D-containing NMDA receptors functionally controls stochastic GABA release and short-term plasticity. We also demonstrate that GluN2D-containing receptors specifically on PV interneurons mediate the inhibitory synaptic and behavioral responses to low dose ketamine, suggesting that this neuron-type-specific target has therapeutic potential for a host of brain disorders.
Conclusions: GluN2D-containing subunits are functionally localized to presynaptic boutons of interneurons in the hippocampus. Novel pharmaceutical agents to activate GluN2D, and thus increase inhibitory tone, represent a novel therapeutic approach in the epilepsy field.
Funding: NIH-NIA (Rowan)
NIH-NIMH (Traynelis)