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Vol. 302, Issue 3, 1037-1045, September 2002
1 Subunit Knockout Mice
Departments of Pharmacology (J.E.K., A.L.M.) and Psychiatry
(A.L.M.), Bowles Center for Alcohol Studies (J.E.K., T.K.O., A.L.M.),
University of North Carolina, Chapel Hill, North Carolina; Department
of Pharmacology and Clinical Pharmacology, University of Turku, Turku,
Finland (E.R.K.); and Department of Anesthesiology, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (G.E.H.)
GABAA receptors mediate fast inhibitory neurotransmission
in the central nervous system (CNS), and approximately half of these receptors contain 
1 subunits. GABAA receptor 1
subunits are important for receptor assembly and specific
pharmacological responses to benzodiazepines. Plasticity in
GABAA receptor 1 subunit expression is associated with
changes in CNS excitability observed during normal brain
development, in animal models of epilepsy, and upon withdrawal
from alcohol and benzodiazepines. To examine the role of
1 subunit-containing GABAA receptors in vivo, we
characterized receptor subunit expression and pharmacological
properties in cerebral cortex of knockout mice with a targeted deletion
of the 1 subunit. The mice are viable but exhibit an intention
tremor. Western blot analysis confirms the complete loss of 1
subunit peptide expression. Stable adaptations in the expression of
several GABAA receptor subunits are observed in the fifth
to seventh generations, including decreased expression of 
2/3 and
2 subunits and increased expression of 2 and 3 subunits.
There was no change in 4, 5, or 
subunit peptide levels in
cerebral cortex. Knockout mice exhibit loss of over half of
GABAA receptors measured by [3H]muscimol,
[3H]2-(3-carboxyl)-3-amino-6-(4-methoxyphenyl)-pyridazinium
bromide ([3H]SR-95531), and
t-butylbicyclophosphoro[35S]thionate
([35S]TBPS) binding.
[3H]Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate ([3H]Ro15-4513) binding is reduced by variable amounts in
different regions across brain. GABAA receptor
1
/ mice lose all high-affinity
[3H]zolpidem binding and about half of
[3H]flunitrazepam binding in the cerebral cortex. The
potency and maximal efficacy of muscimol-stimulated
36Cl uptake in cerebral cortical
synaptoneurosomes are reduced in 1/ mice.
Furthermore, knockout mice exhibit increased bicuculline-induced seizure susceptibility compared with wild-type mice. These data emphasize the significance of 1 subunit expression and its
involvement in the regulation of CNS excitability.
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