A schizophrenia-related sensorimotor deficit links α3-containing GABAAreceptors to a dopamine hyperfunction

Kay Yan Benjamin Yee, R. Keist, L. Von Boehmer, R. Studer, D. Benke, N. Hagenbuch, Y. Dong, R. C. Malenka, J. M. Fritschy, H. Bluethmann, J. Feldon, H. Möhler, U. Rudolph

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156 Citations (Scopus)

Abstract

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the α3 subunit of the GABAAreceptor. α3 knockout (α3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABAA-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by α2-containing GABAAreceptors, was preserved. As a result of the loss of α3 GABAAreceptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in α3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the α3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in α3KO mice compared with WT mice. These results suggest that the absence of α3-subunit- containing GABAAreceptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at α3-containing GABAAreceptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.
Original languageEnglish
Pages (from-to)17154-17159
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number47
DOIs
Publication statusPublished - 22 Nov 2005
Externally publishedYes

Keywords

  • Haloperidol
  • Sensorimotor gating

ASJC Scopus subject areas

  • General

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