Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice.
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.
Singer
Philipp
P
Laboratory of Behavioural Neurobiology, Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland.
Boison
Detlev
D
Möhler
Hanns
H
Feldon
Joram
J
Yee
Benjamin K
BK
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics*; D006185:Habituation, Psychophysiologic / Q000235:genetics; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D016548:Prosencephalon / Q000378:metabolism*; D013216:Reflex, Startle / Q000235:genetics; D055139:Sensory Gating / Q000235:genetics*
D018691:Excitatory Amino Acid Antagonists; D050487:Glycine Plasma Membrane Transport Proteins; C493267:Slc6a9 protein, mouse; D016291:Dizocilpine Maleate