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The Journal of Neuroscience, March 23, 2005, 25(12):3234-3245; doi:10.1523/JNEUROSCI.3364-04.2005

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Neurobiology of Disease
GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

Chi-Sung Chiu,^1,6 Stephen Brickley,² Kimmo Jensen,^3,4 Amber Southwell,¹ Sheri Mckinney,¹ Stuart Cull-Candy,⁵ Istvan Mody,³ and Henry A. Lester¹

¹Division of Biology, California Institute of Technology, Pasadena, California 91125, ²Biophysics Section, Imperial College London, London SW7 2AZ, United Kingdom, ³Departments of Neurology and Physiology, School of Medicine, University of California Los Angeles, Los Angeles, California 90095-1769, ⁴Department of Physiology, University of Aarhus, DK-8000 Aarhus C, Denmark, ⁵Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, and ⁶Department of Neurobiology, Merck Research Laboratories, West Point, Pennsylvania 19486

GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA_A receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA_A-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

Key words: tiagabine; epilepsy; flunitrazepam; cerebellum; inhibition; tremor

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Received Aug 16, 2004; revised January 25, 2005; accepted January 25, 2005.

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