A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction.
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 alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO 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 alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.
Yee
B K
BK
Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Keist
R
R
von Boehmer
L
L
Studer
R
R
Benke
D
D
Hagenbuch
N
N
Dong
Y
Y
Malenka
R C
RC
Fritschy
J-M
JM
Bluethmann
H
H
Feldon
J
J
Möhler
H
H
Rudolph
U
U
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D018757:GABA Modulators / Q000494:pharmacology; D018390:Gene Targeting; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D015640:Ion Channel Gating / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D021122:Protein Subunits / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*
D014151:Anti-Anxiety Agents; D018757:GABA Modulators; C546258:Gabra3 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000661:Amphetamine; D006220:Haloperidol; D003975:Diazepam; D004298:Dopamine