title: A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism.
abstract: Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist d-cycloserine has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that rats selectively bred for low rates of play-induced pro-social ultrasonic vocalizations (USVs) can be used to model certain core symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play-induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to play a functional role in autism, and GLYX-13 shows promise for the treatment of autism. We dedicate this paper to Ole Ivar Lovaas (May 8, 1927-August 2, 2010), a pioneer in the field of autism.
authors: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL 60201, USA. j-moskal@nothwestern.edu
authors: Joseph R
authors: JR
authors: Moskal
authors: Jeffrey
authors: J
authors: Burgdorf
authors: Roger A
authors: RA
authors: Kroes
authors: Stefan M
authors: SM
authors: Brudzynski
authors: Jaak
authors: J
authors: Panksepp
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D004723:Endorphins / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D009842:Oligopeptides / Q000627:therapeutic use*; D010988:Play and Playthings / Q000523:psychology; D051381:Rats; D018009:Receptors, Glycine / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D014828:Vocalization, Animal / Q000187:drug effects / Q000502:physiology
chemical_list: D004723:Endorphins; D009842:Oligopeptides; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C507283:GLYX-13 peptide