GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum.
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.
Chiu
Chi-Sung
CS
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Brickley
Stephen
S
Jensen
Kimmo
K
Southwell
Amber
A
Mckinney
Sheri
S
Cull-Candy
Stuart
S
Mody
Istvan
I
Lester
Henry A
HA
D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001259:Ataxia / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology; D001569:Benzodiazepines / Q000627:therapeutic use; D001831:Body Temperature / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000503:physiopathology*; D004558:Electric Stimulation / Q000379:methods; D004569:Electroencephalography; D005106:Exploratory Behavior / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007266:Inhibition, Psychological; D007527:Isoenzymes / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000502:physiology / Q000528:radiation effects; D010433:Pentylenetetrazole; D011597:Psychomotor Performance / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism; D012022:Reflex, Acoustic / Q000235:genetics; D045442:Rotarod Performance Test / Q000379:methods; D012640:Seizures / Q000139:chemically induced; D013574:Synaptosomes / Q000378:metabolism; D014202:Tremor / Q000188:drug therapy / Q000235:genetics*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D007527:Isoenzymes; D011724:Pyridazines; D011963:Receptors, GABA-A; C493419:Slc6a13 protein, mouse; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; C049853:gabazine; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D010433:Pentylenetetrazole