TY - JOUR T1 - Disruption of Glycine Transporter 1 Restricted to Forebrain Neurons Is Associated with a Procognitive and Antipsychotic Phenotypic Profile JF - The Journal of Neuroscience JO - J. Neurosci. SP - 3169 LP - 3181 DO - 10.1523/JNEUROSCI.5120-05.2006 VL - 26 IS - 12 AU - Benjamin K. Yee AU - Ela Balic AU - Philipp Singer AU - Cornelia Schwerdel AU - Thomas Grampp AU - Laetitia Gabernet AU - Irene Knuesel AU - Dietmar Benke AU - Joram Feldon AU - Hanns Mohler AU - Detlev Boison Y1 - 2006/03/22 UR - http://www.jneurosci.org/content/26/12/3169.abstract N2 - The NMDA receptor is thought to play a central role in some forms of neuronal plasticity, including the induction of long-term potentiation. NMDA receptor hypofunction can result in mnemonic impairment and has been implicated in the cognitive symptoms of schizophrenia. The activity of NMDA receptors is controlled by its endogenous coagonist glycine, and a local elevation of glycine levels is expected to enhance NMDA receptor function. Here, we achieved this by the generation of a novel mouse line (CamKIIαCre;Glyt1tm1.2fl/fl) with a neuron and forebrain selective disruption of glycine transporter 1 (GlyT1). The mutation led to a significant reduction of GlyT1 and a corresponding reduction of glycine reuptake in forebrain samples, without affecting NMDA receptor expression. NMDA (but not AMPA) receptor-evoked EPSCs recorded in hippocampal slices of mutant mice were 2.5 times of those recorded in littermate controls, suggesting that neuronal GlyT1 normally assumes a specific role in the regulation of NMDA receptor responses. Concomitantly, the mutants were less responsive to phencyclidine than controls. The mutation enhanced aversive Pavlovian conditioning without affecting spontaneous anxiety-like behavior in the elevated plus maze and augmented a form of attentional learning called latent inhibition in three different experimental paradigms: conditioned freezing, conditioned active avoidance, conditioned taste aversion. The CamKIIαCre;Glyt1tm1.2fl/fl mouse model thus suggests that augmentation of forebrain neuronal glycine transmission is promnesic and may also offer an effective therapeutic intervention against the cognitive and attentional impairments characteristic of schizophrenia. ER -