Metabotropic functions of the NMDA receptor and an evolving rationale for exploring NR2A-selective positive allosteric modulators for the treatment of autism spectrum disorder

NMDA receptors are widely distributed throughout the brain and major therapeutic challenges include targeting specific NMDA receptor subtypes while preserving spatial and temporal specificity during their activation. The NR2A-subunit containing NMDA receptor is implicated in regulating synchronous oscillatory output of cortical pyramidal neurons, which may be disturbed in clinical presentations of autism spectrum disorder (ASD). Because NR2A-selective positive allosteric modulators (PAMs) preserve spatial and temporal selectivity while activating this subpopulation of receptors, they represent a promising strategy to address neocortical circuit abnormalities in ASD. In addition to promoting Ca2+ entry and membrane depolarization, diverse metabotropic effects of NMDA receptor activation on signal transduction pathways occur within the cell, some of which depend on alignment of protein binding partners. For example, NMDA receptor agonist interventions attenuate impaired sociability in transgenic mice with 'loss-of-function' mutations of the Shank family of scaffolding proteins, which highlights the necessity of a carefully orchestrated alignment of protein binding partners in the excitatory synapse. The current Review considers metabotropic functions of the NMDA receptor that could play a role in sociability and the pathogenesis of ASD (e.g., mTOR signaling), in addition to its more familiar ionotropic functions, and provides a rationale for therapeutic exploration of NR2A-selective PAMs.