Lentiviral vector-mediated rescue of motor behavior in spontaneously occurring hereditary ataxic mice

Hotfoot5J mice are spontaneously occurring ataxic mice that lack delta 2 glutamate receptor (GluR82) protein in cerebellar Purkinje cells. Here we aimed to rescue the ataxic phenotype of hotfoot5J mice by lentiviral vector-mediated expression of recombinant GIuR82 in Purkinje cells. Lentiviral vectors expressing GluR delta 2 were injected into the cerebellar cortex of hotfoot5J mice 6 or 7 days after birth, and the effects were studied on postnatal day 30. The motor behavior of hotfoot5J mice treated with vectors expressing GluR82 was markedly rescued, whereas the ataxia of hotfoot5J mice treated with vectors expressing GFP was comparable to that of non-injected hotfoot5J littermates. Furthermore, the impaired release probability of glutamate from parallel fiber terminals and the failure of developmental elimination of surplus climbing fibers from Purkinje cells in hotfoot5J mice were completely rescued by GIuR82 expression. These results indicate the therapeutic potential of viral vector-based gene therapy for hereditary cerebellar ataxia and other neuronal disorders. (C) 2009 Elsevier Inc. All rights reserved.