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The Journal of Neuroscience, July 30, 2003, 23(17):6759-6767

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Reversible Suppression of Glutamatergic Neurotransmission of Cerebellar Granule Cells In Vivo by Genetically Manipulated Expression of Tetanus Neurotoxin Light Chain

Mutsuya Yamamoto,^1,2,3 Norio Wada,² Yasuji Kitabatake,³ Dai Watanabe,³ Masayuki Anzai,⁴ Minesuke Yokoyama,⁵ Yutaka Teranishi,⁵ and Shigetada Nakanishi^2,3

¹Mitsubishi Pharma Corporation, Discovery Technology Laboratory, Yokohama, 227-0033, Japan, ²Department of Molecular and System Biology, Kyoto University Graduate School of Biostudies, Kyoto, 606-8501, Japan, ³Department of Biological Sciences, Kyoto University Faculty of Medicine, Kyoto, 606-8501, Japan, ⁴GenCom Corporation, Machida, 194-8511, Japan, and ⁵Mitsubishi Kagaku Institute of Life Sciences, Machida, 194-8511, Japan

We developed a novel technique that allowed reversible suppression of glutamatergic neurotransmission in the cerebellar network. We generated two lines of transgenic mice termed Tet and TeNT mice and crossed the two transgenic lines to produce the Tet/TeNT double transgenic mice. In the Tet mice, the tetracycline-controlled reverse activator (rtTA) was expressed selectively in cerebellar granule cells by the promoter function of the GABA_A receptor 6 subunit gene. In the TeNT mice, the fusion gene of tetanus neurotoxin light chain (TeNT) and enhanced green fluorescent protein (EGFP) was designed to be induced by the interaction of doxycycline (DOX)-activated rtTA with the tetracycline-responsive promoter. The Tet/TeNT mice grew normally even after DOX treatment and exhibited a restricted DOX-dependent expression of TeNT in cerebellar granule cells. Along with this expression, TeNT proteolytically cleaved the synaptic vesicle protein VAMP2 (also termed synaptobrevin2) and reduced glutamate release from granule cells. Both cleavage of VAMP2/synaptobrevin2 and reduction of glutamate release were reversed by removal of DOX. Among the four genotypes generated by heterozygous crossing of Tet and TeNT mice, only Tet/TeNT mice showed DOX-dependent reversible motor impairments as analyzed with fixed bar and rota-rod tests. Reversible suppression of glutamatergic neurotransmission thus can be manipulated with spatiotemporal accuracy by DOX treatment and removal. These transgenic mice will serve as an animal model to study the cerebellar function in motor coordination and learning.

Key words: transgenic mouse; GABA_A receptor; tetanus neurotoxin; tetracycline-inducible system; cerebellum; granule cell; VAMP2; glutamatergic transmission

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Received Apr. 23, 2003; revised Jun. 3, 2003; accepted Jun. 5, 2003.

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