TY - JOUR
T1 - Modulation of sensorimotor gating in prepulse inhibition by conditional brain glycine transporter 1 deletion in mice
AU - Singer, Philipp
AU - Boison, Detlev
AU - Möhler, Hanns
AU - Feldon, Joram
AU - Yee, Benjamin K.
N1 - Funding Information:
Funding for the present study was provided by the Swiss Federal Institute of Technology (ETH) Zurich, the Swiss National Science Foundation (grants 3100AO-100309 and 3100A0-116719) and the National Institutes of Health (NIH) grant MH083973. None of these played any further role in the design of the study, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
PY - 2011/5
Y1 - 2011/5
N2 - 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 (0.2. mg/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.
AB - 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 (0.2. mg/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.
KW - Attention
KW - Glutamate
KW - Glycine
KW - NMDA
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=79953756501&partnerID=8YFLogxK
U2 - 10.1016/j.euroneuro.2010.06.014
DO - 10.1016/j.euroneuro.2010.06.014
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AN - SCOPUS:79953756501
SN - 0924-977X
VL - 21
SP - 401
EP - 413
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 5
ER -
