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At the cellular level, NMDA\u2010type 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 \u03b1 and \u03b2 N\u2010terminal 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\u2010resolution imaging, we reveal that mutant <jats:italic>HTT<\/jats:italic> drives the elevation of extrasynaptic NMDAR clusters located 100\u2013500\u2009nm from the postsynaptic density. This was accompanied by a decline in synaptic NMDAR\u2010mediated currents while surface NMDAR\u2010mediated currents remained unchanged. These effects were induced within 3\u2009days of mutant <jats:italic>HTT<\/jats:italic> expression in rat hippocampal neurons in vitro, and were specific for NMDARs and not observed with AMPARs. Intriguingly, upregulation of either \u03b1\u2010 or \u03b2SAP97 expression increased synaptic and\/or perisynaptic NMDAR localization and prevented the shift of NMDARs to extrasynaptic sites in mutant <jats:italic>HTT<\/jats:italic> neurons. This was accompanied by the rescue of normal synaptic NMDAR\u2010mediated currents. Taken together, our high\u2010resolution data reveals plasticity in surface NMDAR localization driven by mutant <jats:italic>HTT<\/jats:italic> and identifies the similar but independent roles of SAP97 N\u2010terminal isoforms in maintaining normal synaptic function in pathological states.<\/jats:p>","DOI":"10.1002\/hipo.22995","type":"journal-article","created":{"date-parts":[[2018,8,3]],"date-time":"2018-08-03T12:15:47Z","timestamp":1533298547000},"page":"707-723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["SAP97\u2010mediated rescue of NMDA receptor surface distribution in a neuronal model of Huntington's disease"],"prefix":"10.1002","volume":"28","author":[{"given":"Wojciech","family":"Ambroziak","sequence":"first","affiliation":[{"name":"Department of Physiology and Centre for Brain Research The University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantelle","family":"Fourie","sequence":"additional","affiliation":[{"name":"Department of Physiology and Centre for Brain Research The University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8714-7456","authenticated-orcid":false,"given":"Johanna M.","family":"Montgomery","sequence":"additional","affiliation":[{"name":"Department of Physiology and Centre for Brain Research The University of Auckland  Auckland New 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