Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition

Abstract

Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In a5(H105R) mutant mice, the expression of the a5 subunit-containing GABA A receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in a5(H105R) mutant mice. These effects were apparent in both genders. Thus, a5 subunit-containing GABA A receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of a5 GABA A receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of a5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

“…Targeted deletion of the a5-subunit causes alterations in learning and memory processes, consistent with alterations in normal HPC functions. Mice with mutations of the a5-subunit display impairments in latent inhibition, prepulse inhibition, and extinction of fear behaviors (Gerdjikov et al, 2008;Hauser et al, 2005). Consequently, with otherwise normal HPC activity, loss of the a5-subunit has behavioral consequences in the processing of contextual stimuli.…”

“…Antagonism or genetic deletion of a5GABA A R has behavioral consequences that resemble some of the behavioral abnormalities seen in schizophrenia, including reduced prepulse inhibition to startle (Hauser et al, 2005) and impaired latent inhibition (Gerdjikov et al, 2008). In the present study, we use the MAM model to demonstrate the effectiveness of a novel compound, SH-053-2 0 F-R-CH3, in restoring normal HPC activity and secondary spontaneous DA activity.…”

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

“…The test was conducted under a constant 65-dB[A] background noise and comprised a mixture of different trial types, as described in ref. 17. The efficacy of haloperidol (0.2 mg͞kg i.p.…”

Disruption of Glycine Transporter 1 Restricted to Forebrain Neurons Is Associated with a Procognitive and Antipsychotic Phenotypic Profile

“…Experiment 5: locomotor reaction to systemic amphetamine and phencyclidine. The apparatus consisted of four open-field white wooden square arenas (40 ϫ 40 cm) as described previously (Hauser et al, 2005). Amphetamine (2.5 mg/kg), phencyclidine (5 mg/kg), or vehicle saline solution (0.9% NaCl) was administered via the intraperitoneal route (at an injection volume of 5 ml/kg) immediately before testing.…”