AMPA RECEPTOR DESENSITIZATION PREDICTS THE SELECTIVE VULNERABILITY OFCEREBELLAR PURKINJE-CELLS TO EXCITOTOXICITY

Cerebellar Purkinje cells are selectively vulnerable to ischemia, alth ough the reasons for this are unknown, In cultured embryonic rat cereb ellar neurons, the steady state responses to the desensitizing agonist AMPA relative to responses to the nondesensitizing agonist kainate we re greater in Purkinje cells compared to other cells, as measured by w hole cell voltage clamp studies. Fluorimetric [Ca2+](i) imaging experi ments similarly found greater responses to AMPA relative to kainate in Purkinje cells than in other cerebellar neurons, In toxicity experime nts measuring cell survival 24 hr following agonist exposure, AMPA and glutamate produced Ca2+-dependent toxicity which was selective for th e Purkinje cell fraction of the neurons, whereas kainate produced nons elective toxicity, and NMDA selectively spared the mature Purkinje cel ls. Cyclothiazide, which inhibits AMPA receptor desensitization, enhan ced steady state current responses to AMPA and increased the toxicity of AMPA, We conclude that the vulnerability of cerebellar neurons in c ulture to glutamate agonist-induced toxicity parallels the magnitude o f the steady state currents produced, and that Purkinje cells may be s electively vulnerable because they express AMPA receptors which underg o less complete desensitization.