SAP97-mediated rescue of NMDA receptor surface distribution in a neuronal model of Huntington's disease.

Abstract

Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an expansion of the CAG repeat tract in the HTT gene, leading to motor, cognitive, and psychiatric symptoms. At the cellular level, NMDA-type glutamate receptors are upregulated at glutamatergic extrasynaptic sites in HD, triggering cell death signaling pathways and driving HD neurodegeneration. Extrasynaptic and synaptic glutamate receptor trafficking and surface distribution are regulated by the α and β N-terminal isoforms of SAP97, a postsynaptic density protein localized at glutamatergic synapses. Here we examined the surface distribution of NMDARs and AMPARs in a cellular model of HD, and whether the manipulation of individual SAP97 isoforms can regulate receptor distribution in diseased neurons. Using dSTORM super-resolution imaging, we reveal that mutant HTT drives the elevation of extrasynaptic NMDAR clusters located 100-500 nm from the postsynaptic density. This was accompanied by a decline in synaptic NMDAR-mediated currents while surface NMDAR-mediated currents remained unchanged. These effects were induced within 3 days of mutant HTT expression in rat hippocampal neurons in vitro, and were specific for NMDARs and not observed with AMPARs. Intriguingly, upregulation of either α- or βSAP97 expression increased synaptic and/or perisynaptic NMDAR localization and prevented the shift of NMDARs to extrasynaptic sites in mutant HTT neurons. This was accompanied by the rescue of normal synaptic NMDAR-mediated currents. Taken together, our high-resolution data reveals plasticity in surface NMDAR localization driven by mutant HTT and identifies the similar but independent roles of SAP97 N-terminal isoforms in maintaining normal synaptic function in pathological states.