Regulation of NMDA receptor interactions with the actin cytoskeleton in dendritic spine development

In the central nervous system, the majority of excitatory synapses exist on small actin-enriched structures protruding from dendrites, known as dendritic spines. Actin cytoskeletal rearrangements drive dynamic changes in spine shape, size, and density depending on developmental stage and synaptic activity. Spines initially emerge from the dendritic shaft as dynamic protrusions known as filipodia-like spines, which serve as precursors to mature dendritic spines. The formation and maturation of dendritic spines facilitate information transfer in neural circuits, underlying cognitive processes, such as learning and memory formation, and altered spine development results in neurodevelopmental disorders. Within dendritic spines, signaling events are regulated by many synaptic receptors such as the ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. However, only NMDA receptors are enriched in both immature filopodia-like spine precursors and mature dendritic spines, with AMPA receptors expressed later in development and coinciding with spine maturation. During embryonic development, most NMDA receptors contain GluN2B subunits, in contrast to mature synapses which predominantly contain GluN2A subunits. While many actin regulatory proteins, such as α-actinin-2, interact with NMDA receptor subunits, it remains unclear whether GluN2B vs. GluN2A-containing receptors exhibit differences in their preferential protein interactions that underly dendritic spine development. The following review highlights how preferential interactions between specific GluN2 isoforms and actin cytoskeletal regulators underlie synaptic development by balancing dynamic events of synaptic plasticity with competing events of synaptic strengthening and consolidation. We discuss how alterations in the expression of GluN2 isoforms and/or mutations that disrupt actin interactions contribute to neurological disorders, both developmental and degenerative.