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

Abstract

GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, Ϫ10%; male, Ϫ20%) 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.

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

“…An anxiety-prone behavior, which differed from our results with the open field and EPM tests, was observed in these mice (Jensen et al, 2003). These differences may be attributed to the different genetic background between the two mutant mice strains (C57BL/6J in the studies of Chiu et al (2005), whereas, mixed C57BL/6J and 129SvJ genetic background mice were used in our studies). However, the different strategy for making GAT1 knockout mice could contribute to the results of different phenotype.…”

“…Behavioral tests showed that GAT1-deficiency causes tremor, ataxia, and nervousness (Chiu et al, 2005). Nevertheless, there is little direct evidence to show the role of GAT1 in the pathogenesis of depression and anxiety.…”

Molecular Targets for Antiepileptic Drug Development

“…329 Thus, the long-term antiepileptic action of tiagabine may be mediated by potentiation of the tonic inhibitory effect of GABA in the forebrain rather than enhancement of phasic inhibition. 330 Studies with a novel GABA-transporter inhibitor, EF1502, that potently inhibits GAT-1 and GAT-2 (BGT-1)-but not GAT-3 and GAT-4 -indicate that inhibition of GAT-2 potentiates the anticonvulsant activity of GAT-1. 331,332 GAT-3 can be selectively inhibited with SNAP-5114, which enhances GABA-mediated synaptic inhibition in the neocortex, indicating that GAT-3 plays a role in this brain region.…”

TheCaenorhabditis elegans snf-11Gene Encodes a Sodium-dependent GABA Transporter Required for Clearance of Synaptic GABA

“…The loss of GAT1 function in mice results in significant neurological defects, including tremors, ataxia, and anxiety (Chiu et al, 2005). The reduced GABA uptake activity results in elevated extracellular GABA levels, which in turn result in an increased GABA A receptor-mediated tonic conductance in cerebellar granule and Purkinje cells (Chiu et al, 2005;also Jensen et al, 2003).…”

“…The reduced GABA uptake activity results in elevated extracellular GABA levels, which in turn result in an increased GABA A receptor-mediated tonic conductance in cerebellar granule and Purkinje cells (Chiu et al, 2005;also Jensen et al, 2003). Jensen et al (2003) also report that GAT1-deficient mice lack a presynaptic GABA B -mediated conductance.…”