Neuroscience and Biobehavioral Reviews 35 (2011) 1982–1988 Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev Review A novel NMDA receptor glycine-site partial agonist, GLYX-13, has therapeutic potential for the treatment of autism Joseph R. Moskal a,∗, Jeffrey Burgdorf a, Roger A. Kroes a, Stefan M. Brudzynski b, Jaak Panksepp a,c a Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, IL 60201, United States b Department of Psychology, Brock University, St. Catharines, Ontario, L2S 3A1 Canada c Department of Veterinary Comparative Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine Washington State University, Pullman, WA 99163, United States article info abstract Article history: Deficits in social approach behavior, rough-and-tumble play, and speech abnormalities are core features Received 18 November 2010 of autism that can be modeled in laboratory rats. Human twin studies show that autism has a strong Received in revised form 8 June 2011 genetic component, and a recent review has identified 99 genes that are dysregulated in human autism. Accepted 10 June 2011 Bioinformatic analysis of these 99 genes identified the NMDA receptor complex as a significant interaction d We dedicate this paper to Ole Ivar Lovaas hub based on protein-protein interactions. The NMDA receptor glycine site partial agonist -cycloserine (May 8, 1927−August 2, 2010), a pioneer in has been shown to treat the core symptom of social withdrawal in autistic children. Here, we show that the field of autism. 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 Keywords: conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of Autism non-frequency modulated (i.e. monotonous) ultrasonic vocalizations, compared to non-selectively bred NMDA random-line animals. Gene expression patterns in the low-line animals show significant enrichment in Vocalizations autism-associated genes and the NMDA receptor family was identified as a significant hub. Treatment GLYX-13 of low-line animals with the NMDAR glycine site partial agonist GLYX-13 rescued the deficits in play- Rough-and-tumble play induced pro-social 50-kHz and reduced monotonous USVs. Thus, the NMDA receptor has been shown to Microarray play a functional role in autism, and GLYX-13 shows promise for the treatment of autism. We dedicate Rats this paper to Ole Ivar Lovaas (May 8, 1927–August 2, 2010), a pioneer in the field of autism. © 2011 Elsevier Ltd. All rights reserved. Contents 1. Introduction ........................................................................................................................................ 1982 2. Brain opioids and autism .......................................................................................................................... 1983 3. NMDA receptors play a functional role in autism ................................................................................................. 1984 4. Low-line rats show an autism-like phenotype and gene expression patterns.................................................................... 1984 5. GLYX-13 reverses the autistic-like symptoms of low-line animals ............................................................................... 1984 6. Summary and conclusions ......................................................................................................................... 1987 Acknowledgements................................................................................................................................ 1987 References ......................................................................................................................................... 1987 1. Introduction patterns of behavior (Wing and Gould, 1979). Autism is now considered to be a developmental disorder and is highly inherita- Autism is characterized by impairments in social interac- ble, with presently unknown environmental exacerbating vectors. tion, communication, and restricted, repetitive, and stereotyped Twin studies show strong genetic heritability for autism. The con- cordance for autism is 60–91% in monozygotic twins compared to 0–10% in dizygotic twins, and 0.3% in the general population ∗ (CDC, 2009; Ritvo et al., 1985; Rosenberg et al., 2009). To date, 99 Corresponding author at: Falk Center for Molecular Therapeutics, Northwestern autism candidate genes have been identified by human genome University, Department of Biomedical Engineering, 1801 Maple Ave, Suite 4300, Evanston, IL 60201, United States. Tel.: +1 847 491 4802; fax: +1 847 491 4810. linking studies and human gene expression profiling by microar- E-mail address: [email protected] (J.R. Moskal). ray (Lee et al., 2009). These include synaptic development genes, 0149-7634/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2011.06.006 J.R. Moskal et al. / Neuroscience and Biobehavioral Reviews 35 (2011) 1982–1988 1983 neurotransmission genes, and neurotrophic genes, among others. autism, namely the brain opioid dysregulation theory of impaired Like other psychiatric disorders, the individual autism candidate social behavior and affect. genes have “weak penetrance” with only a subset of autistic chil- dren showing an abnormality in any individual candidate gene (Meyer-Lindenberg and Weinberger, 2006). A key challenge is to 2. Brain opioids and autism identify which of these autism candidate genes are functionally linked to autism and could therefore be pursued as a therapeutic The increasing opportunities that new strategies for gene dis- target. For instance, bioinformatics tools can now be used to iden- covery in psychiatric disorders can now be combined with theory tify autism candidate genes that have been shown to have a greater driven preclinical models of autism spectrum disorders that focus number of protein–protein interactions with other autism candi- on the potential neurochemical changes that may mediate autistic date genes, called hub genes. It has been hypothesized that these symptoms. Because of recent advances in affective neuroscience, hub genes can serve as “master switches” that control biological the core psychological deficits found in autistic disorders can now function (Borneman et al., 2006). be considered in conjunction with the more easily studied behav- Pharmacological-based therapeutics have had limited success ioral features (Panksepp, 1998). This strategy led to the recognition and substantial side effects. Currently, behavioral modification that brain opioids mediate social bonding, with the recognition that techniques have been the most powerful positive interventions for naltrexone may promote social motivation in a subset of autistic autism spectrum disorders (Lovaas, 1987; Lovaas and Simmons, children (Elchaar et al., 2006). 1969). The antipsychotic risperidone is the only FDA approved Prior to the advent of modern neuro-genetic approaches, pre- medication for autism, and has been reported to (i) significantly clincial models had to rely exclusively on simulation of symptoms. decrease hyperactivity and irritability symptoms, (ii) have little to The first animal model of autism that yielded a positive therapeu- no effect on inappropriate speech or social withdrawal, and (iii) tic effect in humans, followed the dictum that autism reflected a show significant weight gain and sedative side effects (Jesner et al., neural deficit in the neurochemical mechanisms of social related- 2007). ness (Panksepp, 1981). Thirty years ago, it was clear that modest Perhaps the next most effective treatment in facilitating pro- doses of opioid agonists could yield autistic symptoms in animals, social responsivity in a subset of autistic children is the off-label including diminished pain, social motivation, communication and use of the opiate receptor antagonist naltrexone (Elchaar et al., attachment, with some elevation of stereotyped behavioral ten- 2006; Panksepp et al., 1991; Rossignol, 2009). This notion is dencies (from Moles et al., 2004; Panksepp et al., 1980). Social based on the first animal model of autism ever developed which affect and communication were clearly modulated by endogenous was derived from emerging understanding of the opioid neuro- opioids (Keverne et al., 1989; Wohr et al., 2011). The ability of chemistries that regulate social affect and motivation (Bouvard opioid antagonists to increase certain aspects of social engage- et al., 1995; Brambilla et al., 1997; Cazzullo et al., 1999; Gillberg ment and communication suggested the possibility of beneficially et al., 1985; Leboyer et al., 1999; Tordjman et al., 1997). More recent up-regulating social motivation with low doses of orally available work on other neurochemical mechanisms that regulate social opiate receptor antagonists such as naltrexone (Panksepp, 1979; processes has identified oxytocin as a promising candidate for Panksepp and Sahley, 1987). beneficial modulation of autistic symptoms (Green and Hollander, Small open-trials were promising, with optimal prosocial 2010; Panksepp, 1992). Genetic analysis has highlighted one oxy- effects at quite low doses (e.g., ∼0.25 mg/kg p.o. given every other tocin secretary allele that leads to reduced plasma oxytocin, and in day, with