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First published on October 26, 2007; DOI: 10.1124/mol.107.038828

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Received for publication June 6, 2007.
Revised October 4, 2007.
Accepted for publication October 26, 2007.

Cortical glutamatergic neurons mediate the motor sedative action of diazepam

Anja Zeller 1, Florence Crestani 1, Isabelle Camenisch 1, Takuji Iwasato 2, Shigeyoshi Itohara 2, Uwe Rudolph 3*, Jean-Marc Fritschy 4

1 University of Zurich, Institute of Pharmacology and Toxicology 2 Riken Brain Science Institute 3 Mclean Hospital, Laboratory of Genetic Neuropharmacology 4 University of Zurich

* Address correspondence to: E-mail: urudolph{at}mclean.harvard.edu

Abstract

The neuronal circuits mediating the sedative action of diazepam are unknown. While the motor depressant action of diazepam is suppressed in {alpha}1(H101R) homozygous knock-in mice expressing diazepam-insensitive {alpha}1-GABAA receptors, global {alpha}1-knock-out mice show greater motor sedation with diazepam. To clarify this paradox, attributed to compensatory upregulation of the {alpha}2 and {alpha}3 subunits, and further identify the neuronal circuits supporting diazepam-induced sedation, we generated Emx1-cre-recombinase-mediated conditional mutant mice, selectively lacking the {alpha}1 subunit (forebrain-specific {alpha}1-/-) or expressing either a single wildtype (H) or a single point-mutated (R) {alpha}1 allele (forebrain-specific {alpha}1-/H and {alpha}1-/R mice, respectively) in forebrain glutamatergic neurons. In the rest of the brain, {alpha}1-/R mutants are heterozygous {alpha}1(H101R) mice. Forebrain-specific {alpha}1-/- mice showed enhanced diazepam-induced motor depression and increased expression of the {alpha}2 and {alpha}3 subunits in the neocortex and hippocampus, in comparison to their pseudo-wildtype littermates. Forebrain-specific {alpha}1-/R mice were less sensitive than {alpha}1-/H mice to the motor depressing action of diazepam, but each of these conditional mutants had a similar behavioral response as their corresponding control littermates. Unexpectedly, expression of the {alpha}1 subunit was reduced in forebrain, notably in {alpha}1-/R mice, and the {alpha}3 subunit was upregulated in neocortex, indicating that proper {alpha}1 subunit expression requires both alleles. In conclusion, conditional manipulation of GABAA receptor {alpha}1 subunit expression can induce compensatory changes in the affected areas. Specifically, alterations in GABAA receptor expression restricted to forebrain glutamatergic neurons reproduce the behavioral effects seen after a global alteration, thereby implicating these neurons in the motor sedative effect of diazepam.


Key words: GABAA, GABAC, Mutagenesis/Chimeric approaches, Regulation of gene expression, Benzodiazepines




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