Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile

Kay Yan Benjamin Yee, Ela Balic, Philipp Singer, Cornelia Schwerdel, Thomas Grampp, Laetitia Gabernet, Irene Knuesel, Dietmar Benke, Joram Feldon, Hanns Mohler, Detlev Boison

Research output: Journal article publicationJournal articleAcademic researchpeer-review

122 Citations (Scopus)

Abstract

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 enhanceNMDAreceptor 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 andmayalso offer an effective therapeutic intervention against the cognitive and attentional impairments characteristic of schizophrenia.
Original languageEnglish
Pages (from-to)3169-3181
Number of pages13
JournalJournal of Neuroscience
Volume26
Issue number12
DOIs
Publication statusPublished - 22 Mar 2006
Externally publishedYes

Keywords

  • Conditional knock-out mice
  • Glycine transporter 1
  • Latent inhibition
  • Learning
  • NMDA receptor
  • Schizophrenia
  • Selective attention

ASJC Scopus subject areas

  • Neuroscience(all)

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