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The Journal of Neuroscience, March 22, 2006, 26(12):3169-3181; doi:10.1523/JNEUROSCI.5120-05.2006

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Behavioral/Systems/Cognitive
Disruption of Glycine Transporter 1 Restricted to Forebrain Neurons Is Associated with a Procognitive and Antipsychotic Phenotypic Profile

Benjamin K. Yee,¹ Ela Balic,² Philipp Singer,¹ Cornelia Schwerdel,² Thomas Grampp,² Laetitia Gabernet,² Irene Knuesel,¹ Dietmar Benke,² Joram Feldon,¹ Hanns Mohler,^2,3 and Detlev Boison⁴

¹Laboratory of Behavioral Neurobiology, Swiss Federal Institute of Technology, 8603 Schwerzenbach, Switzerland, ²Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, ³Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology and Collegium Helveticum, 8093 Zurich, Switzerland, and ⁴R. S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232

Correspondence should be addressed to Dr. Detlev Boison, Dow Neurobiology Laboratories, Legacy Research, 1225 Northeast 2nd Avenue, Portland, OR 97232. Email: dboison{at}downeurobiology.org

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 (CamKIICre;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 CamKIICre;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.

Key words: glycine transporter 1; NMDA receptor; conditional knock-out mice; latent inhibition; selective attention; learning; schizophrenia

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Received Dec. 1, 2005; revised Jan. 12, 2006; accepted Feb. 6, 2006.

Correspondence should be addressed to Dr. Detlev Boison, Dow Neurobiology Laboratories, Legacy Research, 1225 Northeast 2nd Avenue, Portland, OR 97232. Email: dboison{at}downeurobiology.org

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				I. Gaisler-Salomon, S. A. Schobel, S. A. Small, and S. Rayport How High-Resolution Basal-State Functional Imaging Can Guide the Development of New Pharmacotherapies for Schizophrenia Schizophr Bull, November 1, 2009; 35(6): 1037 - 1044. [Abstract] [Full Text] [PDF]

				E. Fernandez-Sanchez, J. Martinez-Villarreal, C. Gimenez, and F. Zafra Constitutive and Regulated Endocytosis of the Glycine Transporter GLYT1b Is Controlled by Ubiquitination J. Biol. Chem., July 17, 2009; 284(29): 19482 - 19492. [Abstract] [Full Text] [PDF]

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				M. Mezler, W. Hornberger, R. Mueller, M. Schmidt, W. Amberg, W. Braje, M. Ochse, H. Schoemaker, and B. Behl Inhibitors of GlyT1 Affect Glycine Transport via Discrete Binding Sites Mol. Pharmacol., December 1, 2008; 74(6): 1705 - 1715. [Abstract] [Full Text] [PDF]

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