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

By C. Chiu, S. Brickley, K. Jensen, Amber L. Southwell, S. Mckinney, S. Cull-Candy, István Módy, H. Lester. 2005

230 citations recorded by the source corpus.

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 GABAA 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 GABAA-, 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

Re-evaluating circuit mechanisms underlying pattern separation (2019, neutral): “Consistent with this, decreasing the excitability of cerebellar granule cells by increasing inhibition is associated with ataxia in GABA transporter 1 knockout mice (Chiu et al., 2005).”
Network Structure within the Cerebellar Input Layer Enables Lossless Sparse Encoding (2014, background): “Deletion of the GABA transporter GAT1 increased tonic inhibition in GCs by 4-fold and was associated with tremor and ataxia (Chiu et al., 2005).”
Purkinje cells directly inhibit granule cells in specialized regions of the cerebellar cortex (2016, unknown): “…GABA release from neurons is not a major source of ambient GABA, but instead GABA release from astrocytes (Lee et al., 2010; Rossi et al., 2003) and the activity of GABA transporters (Attwell et al., 1993; Chiu et al., 2005; Rossi et al., 2003) control ambient GABA levels and tonic inhibition.”