Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice

Singer, Philipp; Boison, Detlev; Möhler, Hanns; Feldon, Joram; Yee, Benjamin K.

doi:10.1016/j.euroneuro.2010.06.014

« Previous Next »European Neuropsychopharmacology
Volume 21, Issue 5 , Pages 401-413, May 2011

Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice

Philipp Singer
- Laboratory of Behavioural Neurobiology, Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland
Detlev Boison
- R.S. Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Ave, Portland OR 97232, United States
Hanns Möhler
- Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
- Institute of Pharmaceutical Sciences, Collegium Helveticum, Semper-Sternwarte, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland
- Federal Institute of Technology Zurich, Semper-Sternwarte, Schmelzbergstrasse 25, CH-8092 Zurich, Switzerland
Joram Feldon
- Laboratory of Behavioural Neurobiology, Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland
Benjamin K. Yee
- Laboratory of Behavioural Neurobiology, Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland
- Corresponding author. Tel.: +41 44 655 74 17; fax: +41 44 655 72 03.

Received 20 November 2009; received in revised form 21 June 2010; accepted 23 June 2010. published online 21 July 2010.

Abstract

Inhibition of glycine transporter 1 (GlyT1) augments N-methyl-D-aspartate receptor (NMDAR)-mediated transmission and represents a potential antipsychotic drug target according to the NMDAR hypofunction hypothesis of schizophrenia. Preclinical evaluation of GlyT1 inhibiting drugs using the prepulse inhibition (PPI) test, however, has yielded mixed outcomes. Here, we tested for the first time the impact of two conditional knockouts of GlyT1 on PPI expression. Complete deletion of GlyT1 in the cerebral cortices confers resistance to PPI disruption induced by the NMDAR blocker MK-801 (0.2mg/kg, i.p.) without affecting PPI expression in unchallenged conditions. In contrast, restricting GlyT1 deletion to neurons in forebrain including the striatum significantly attenuated PPI, and the animals remained sensitive to the PPI-disruptive effect of MK-801 at the same dose. These results demonstrate in mice that depending on the regional and/or cell-type specificity, deletion of the GlyT1 gene could yield divergent effects on PPI.