title: Glycine transporter 1 as a potential therapeutic target for schizophrenia-related symptoms: evidence from genetically modified mouse models and pharmacological inhibition.
abstract: Schizophrenia is characterized by positive symptoms such as hallucinations, negative symptoms such as blunted affect, and symptoms of cognitive deficiency such as deficits in working memory and selective attention. N-methyl-d-aspartate receptor (NMDAR) hypofunction has been implicated in all three pathophysiological aspects of the disease. Due to the severe side effects of direct NMDAR agonists, targeting the modulatory co-agonist glycine-B site of the NMDAR is considered to be a promising strategy to ameliorate NMDAR hypofunction. To assess the antipsychotic and pro-cognitive potential of this approach, we examine the strategies designed to enhance glycine-B site occupancy through glycine transporter 1 (GlyT1) blockade. Among the existing transgenic mouse models with GlyT1 deficits, the one specifically targeting forebrain neuronal GlyT1 has yielded the most promising data on cognitive enhancement. Parallel advances in the pharmacology of GlyT1 inhibition point not only to an enhancement of attention, learning and memory but also include suggestions of mood enhancing effects that might be valuable for treating negative symptoms. Thus, interventions at GlyT1 are highly effective in modifying multiple brain functions, and dissection of their respective mechanisms is expected to further maximize their therapeutic potential for human mental diseases.
authors.affiliation: Institute of Pharmacology, University and ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. mohler@pharma.uzh.ch
authors.forename: Hanns
authors.initials: H
authors.lastname: Möhler
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.forename: Philipp
authors.initials: P
authors.lastname: Singer
authors.forename: Joram
authors.initials: J
authors.lastname: Feldon
authors.forename: Meike
authors.initials: M
authors.lastname: Pauly-Evers
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D050487:Glycine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics; D007858:Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D012559:Schizophrenia / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; C493267:Slc6a9 protein, mouse