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

Chiu, Chi-Sung and Brickley, Stephen and Jensen, Kimmo and Southwell, Amber and McKinney, Sheri and Cull-Candy, Stuart and Mody, Istvan and Lester, Henry A. (2005) GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum. Journal of Neuroscience, 25 (12). pp. 3234-3245. ISSN 0270-6474. PMCID PMC6725086. doi:10.1523/jneurosci.3364-04.2005. https://resolver.caltech.edu/CaltechAUTHORS:20200506-072848149

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1523/jneurosci.3364-04.2005DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6725086PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2005 Society for Neuroscience. Received Aug. 16, 2004; revised Jan. 25, 2005; accepted Jan. 25, 2005. This research was supported by National Institutes of Health Grants DA-01921, NS-11756, MH-49176, NS-030549, and DA-010509, National Science Foundation Grant 0119493, the Wellcome Trust, a Royal Society-Wolfson Award (S.C.-C.), and a Della Martin Fellowship (C.-S.C.). We are indebted to members of Caltech and University of California Los Angeles groups for advice, Limin Shi and Paul Patterson for use and help with the startle system, and J. Crawley for comments on this manuscript.
Funders:
Funding AgencyGrant Number
NIHDA-01921
NIHNS-11756
NIHMH-49176
NIHNS-030549
NIHDA-010509
NSFCBET-0119493
Wellcome TrustUNSPECIFIED
Royal SocietyUNSPECIFIED
Della Martin FoundationUNSPECIFIED
Subject Keywords:tiagabine; epilepsy; flunitrazepam; cerebellum; inhibition; tremor
Issue or Number:12
PubMed Central ID:PMC6725086
DOI:10.1523/jneurosci.3364-04.2005
Record Number:CaltechAUTHORS:20200506-072848149
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200506-072848149
Official Citation:GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum. Chi-Sung Chiu, Stephen Brickley, Kimmo Jensen, Amber Southwell, Sheri Mckinney, Stuart Cull-Candy, Istvan Mody, Henry A. Lester. Journal of Neuroscience 23 March 2005, 25 (12) 3234-3245; DOI: 10.1523/JNEUROSCI.3364-04.2005
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103014
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 May 2020 16:16
Last Modified:16 Nov 2021 18:17

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