Lentiviral vector-mediated rescue of motor behavior in spontaneously occurring hereditary ataxic mice.
Hotfoot5J mice are spontaneously occurring ataxic mice that lack delta2 glutamate receptor (GluRdelta2) protein in cerebellar Purkinje cells. Here we aimed to rescue the ataxic phenotype of hotfoot5J mice by lentiviral vector-mediated expression of recombinant GluRdelta2 in Purkinje cells. Lentiviral vectors expressing GluRdelta2 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 GluRdelta2 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 GluRdelta2 expression. These results indicate the therapeutic potential of viral vector-based gene therapy for hereditary cerebellar ataxia and other neuronal disorders.
Iizuka
Akira
A
Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Takayama
Kiyohiko
K
Torashima
Takashi
T
Yamasaki
Miwako
M
Koyama
Chiho
C
Mitsumura
Kazuhiro
K
Watanabe
Masahiko
M
Hirai
Hirozaku
H
D000818:Animals; D001259:Ataxia / Q000503:physiopathology / Q000628:therapy*; D002531:Cerebellum / Q000503:physiopathology / Q000821:virology*; D049229:Dendritic Spines / Q000502:physiology / Q000821:virology; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D018698:Glutamic Acid / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017628:Microglia / Q000502:physiology / Q000821:virology; D009043:Motor Activity; D009474:Neurons / Q000502:physiology / Q000821:virology; D011689:Purkinje Cells / Q000502:physiology / Q000821:virology; D017470:Receptors, Glutamate / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology / Q000821:virology
D017470:Receptors, Glutamate; D011994:Recombinant Proteins; C107913:glutamate receptor delta 2; D018698:Glutamic Acid