title: Effects of VU0410120, a novel GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in a mouse model of autism.
abstract: The NMDA receptor is a highly regulated glutamate-gated cationic channel receptor that has an important role in the regulation of sociability and cognition. The genetically-inbred Balb/c mouse has altered endogenous tone of NMDA receptor-mediated neurotransmission and is a model of impaired sociability, relevant to Autism Spectrum Disorders (ASDs). Because glycine is an obligatory co-agonist that works cooperatively with glutamate to promote opening of the ion channel, one prominent strategy to promote NMDA receptor-mediated neurotransmission involves inhibition of the glycine type 1 transporter (GlyT1). The current study evaluated the dose-dependent effects of VU0410120, a selective, high-affinity competitive GlyT1 inhibitor, on measures of sociability, cognition and stereotypic behaviors in Balb/c and Swiss Webster mice. The data show that doses of VU0410120 (i.e., 18 and 30mg/kg) that improve measures of sociability and spatial working memory in the Balb/c mouse strain elicit intense stereotypic behaviors in the Swiss Webster comparator strain (i.e., burrowing and jumping). Furthermore, the data suggest that selective GlyT1 inhibition improves sociability and spatial working memory at doses that do not worsen or elicit stereotypic behaviors in a social situation in the Balb/c strain. However, the elicitation of stereotypic behaviors in the Swiss Webster comparator strain at therapeutically relevant doses of VU0410120 suggest that genetic factors (i.e., mouse strain differences) influence sensitivity to GlyT1-elicited stereotypic behaviors, and emergence of intense stereotypic behaviors may be dose-limiting side effects of this interventional strategy.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Burket
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Benson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
authors.forename: Torrian L
authors.initials: TL
authors.lastname: Green
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Jerri M
authors.initials: JM
authors.lastname: Rook
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA, United States. Electronic address: deutscsi@evms.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Deutsch
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D012919:Social Behavior; D065853:Spatial Learning / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects*
chemical_list: D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; D010880:Piperidines; C493267:Slc6a9 protein, mouse; C000604918:VU0410120; C037689:benzamide
keywords: Autism Spectrum Disorders; Balb/c; GlyT1 inhibition; NMDA receptor