aav vector-mediated overexpression of cb1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitoxicityaav vector-mediated过度cb1大麻素受体的海马锥体神经元的防止seizure-induced excitoxicity.pdfVIP

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aav vector-mediated overexpression of cb1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitoxicityaav vector-mediated过度cb1大麻素受体的海马锥体神经元的防止seizure-induced excitoxicity.pdf

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aav vector-mediated overexpression of cb1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitoxicityaav vector-mediated过度cb1大麻素受体的海马锥体神经元的防止seizure-induced excitoxicity

AAV Vector-Mediated Overexpression of CB1 Cannabinoid Receptor in Pyramidal Neurons of the Hippocampus Protects against Seizure-Induced Excitoxicity Stephan Guggenhuber, Krisztina Monory, Beat Lutz*, Matthias Klugmann*¤ Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany Abstract The CB1 cannabinoid receptor is the most abundant G-protein coupled receptor in the brain and a key regulator of neuronal excitability. There is strong evidence that CB1 receptor on glutamatergic hippocampal neurons is beneficial to alleviate epileptiform seizures in mouse and man. Therefore, we hypothesized that experimentally increased CB1 gene dosage in principal neurons would have therapeutic effects in kainic acid (KA)-induced hippocampal pathogenesis. Here, we show that virus-mediated conditional overexpression of CB1 receptor in pyramidal and mossy cells of the hippocampus is neuroprotective and moderates convulsions in the acute KA seizure model in mice. We introduce a recombinant adeno- associated virus (AAV) genome with a short stop element flanked by loxP sites, for highly efficient attenuation of transgene expression on the transcriptional level. The presence of Cre-recombinase is strictly necessary for expression of reporter proteins or CB1 receptor in vitro and in vivo. Transgenic CB1 receptor immunoreactivity is targeted to glutamatergic neurons after stereotaxic delivery of AAV to the dorsal hippocampus of the driver mice NEX-cre. Increased CB1 receptor protein levels in hippocampal lysates of AAV-treated Cre-mice is paralleled by enhanced cannabinoid-induced G-protein activation. KA-induced seizure severity and mortality is reduced in CB1 receptor overexpressors compared with AAV-treated control animals. Neuronal damage in the hippocampal CA3 field is speci