ER-PM Junctions on GABAergic Interneurons Are Organized by Neuregulin 2/VAP Interactions and Regulated by NMDA Receptors.

Neuregulins (NRGs) signal via ErbB receptors to regulate neural development, excitability, synaptic and network activity, and behaviors relevant to psychiatric disorders. Bidirectional signaling between NRG2/ErbB4 and NMDA receptors is thought to homeostatically regulate GABAergic interneurons in response to increased excitatory neurotransmission or elevated extracellular glutamate levels. Unprocessed proNRG2 forms discrete clusters on cell bodies and proximal dendrites that colocalize with the potassium channel Kv2.1 at specialized endoplasmic reticulum-plasma membrane (ER-PM) junctions, and NMDA receptor activation triggers rapid dissociation from ER-PM junctions and ectodomain shedding by ADAM10. Here, we elucidate the mechanistic basis of proNRG2 clustering at ER-PM junctions and its regulation by NMDA receptors. Importantly, we demonstrate that proNRG2 promotes the formation of ER-PM junctions by directly binding the ER-resident membrane tether VAP, like Kv2.1. The proNRG2 intracellular domain harbors two non-canonical, low-affinity sites that cooperatively mediate VAP binding. One of these is a cryptic and phosphorylation-dependent VAP binding motif that is dephosphorylated following NMDA receptor activation, thus revealing how excitatory neurotransmission promotes the dissociation of proNRG2 from ER-PM junctions. Therefore, proNRG2 and Kv2.1 can independently function as VAP-dependent organizers of neuronal ER-PM junctions. Based on these and prior studies, we propose that proNRG2 and Kv2.1 serve as co-regulated downstream effectors of NMDA receptors to homeostatically regulate GABAergic interneurons.

Motor Learning and Physical Exercise in Adaptive Myelination and Remyelination.

The idea that myelination is driven by both intrinsic and extrinsic cues has gained much traction in recent years. Studies have demonstrated that myelination occurs in an intrinsic manner during early development and continues through adulthood in an activity-dependent manner called adaptive myelination. Motor learning, the gradual acquisition of a specific novel motor skill, promotes adaptive myelination in both the healthy and demyelinated central nervous system (CNS). On the other hand, exercise, a physical activity that involves planned, structured and repetitive bodily movements that expend energy and benefits one's fitness, promotes remyelination in pathology, but it is less clear whether it promotes adaptive myelination in healthy subjects. Studies on these topics have also investigated whether the timing of motor learning or physical exercise is important for successful addition of myelin. Here we review our current understanding of the relationship of motor skill learning and physical exercise on myelination.