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J Neurophysiol (March 26, 2003). doi:10.1152/jn.00612.2002
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Submitted on July 29, 2002
Accepted on March 18, 2003

Benzodiazepines Block {alpha}2-Containing Inhibitory Glycine Receptors in Embryonic Mouse Hippocampal Neurons

Liu Lin Thio1*, Ananth Shanmugam2, Keith Isenberg2, and Kelvin Yamada3

1 Departments of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO, USA; Divsion of Pediatric Neurology, St. Louis Children's Hospital, St. Louis, MO, USA
2 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
3 Departments of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA; Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, MO, USA

* To whom correspondence should be addressed. E-mail: thio{at}kids.wustl.edu.

Inhibitory glycine receptors (GlyRs) in the mammalian cortex probably contribute to brain development and to maintaining tonic inhibition. Given their presence throughout the cortex, their modulation likely has important physiological consequences. Although benzodiazepines potentiate {gamma}-aminobutyric acidA receptors (GABAARs), they may also modulate GlyRs since binding studies initially suggested that they act at GlyRs. Furthermore, their diminished ability to potentiate neonatal GABAARs suggests that they may exert their beneficial clinical effects at another site in the developing brain. Therefore, we examined the effect of benzodiazepines on whole-cell currents mediated by GlyRs in cultured embryonic mouse hippocampal neurons. First, we determined the GlyR subunit composition in this preparation. Glycine, {beta}-alanine, and taurine activate strychnine-sensitive, chloride currents in a dose-dependent manner. Maximal concentrations of the three agonists produce equal, non-additive responses as expected of full agonists. The pharmacological properties of the GlyR currents including their pattern of modulation by picrotoxinin, picrotin, and tropisetron indicate that GlyRs consist of {alpha}2{beta} heteromers and {alpha}2 homomers. Reverse transcriptase polymerase chain reaction (RT-PCR) studies confirmed the presence of {alpha}2 and {beta} subunits. Second, we found that micromolar concentrations of some benzodiazepines, including chlordiazepoxide and nitrazepam, inhibit GlyR currents. Nitrazepam inhibition of GlyRs is non-competitve, is not voltage dependent, and does not reflect enhanced desensitization. Thus, benzodiazepines allosterically inhibit {alpha}2-containing GlyRs in embryonic mouse hippocampal neurons via a "low" affinity site.




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