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Infantile NCL (INCL), the most aggressive of these disorders, is caused by mutations in the<jats:italic>CLN1<\/jats:italic>gene that encodes the enzyme palmitoyl protein thioesterase 1 (PPT1). Previous studies have suggested that glutamatergic neurotransmission may be disrupted in INCL, so the present study investigates glutamate receptor function in the<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mouse model of INCL by comparing the sensitivity of cultured wild\u2010type (WT) and<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>cerebellar granule cells to glutamate receptor\u2010mediated toxicity.<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>neurons were significantly less sensitive to AMPA receptor\u2010mediated toxicity but markedly more vulnerable to NMDA receptor\u2010mediated cell death. Because glutamate receptor function is regulated primarily by the surface expression level of the receptor, the surface level of AMPA and NMDA receptor subunits in the cerebella of WT and<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice was also examined. Western blotting of surface cross\u2010linked cerebellar samples showed a significantly lower surface level of the GluR4 AMPA receptor subunit in<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, providing a plausible explanation for the decreased vulnerability of<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>cerebellar neurons to AMPA receptor\u2010mediated cell death. The surface expression of the NR1, NR2A, and NR2B NMDA receptor subunits was similar in the cerebella of WT and<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice, indicating that there is another mechanism behind the increased sensitivity of<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>cerebellar granule cells to NMDA toxicity. Our results indicate an AMPA receptor hypofunction and NMDA receptor hyperfunction phenotype in<jats:italic>Ppt1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>neurons and provide new therapeutic targets for INCL. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22763","type":"journal-article","created":{"date-parts":[[2011,10,4]],"date-time":"2011-10-04T07:37:57Z","timestamp":1317713877000},"page":"367-375","source":"Crossref","is-referenced-by-count":18,"title":["Altered glutamate receptor function in the cerebellum of the<i>Ppt1<\/i><sup>\u2212\/\u2212<\/sup>mouse, a murine model of infantile neuronal ceroid lipofuscinosis"],"prefix":"10.1002","volume":"90","author":[{"given":"Rozzy","family":"Finn","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Attila D.","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David 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