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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1982-1988 |
| Number of pages | 7 |
| Journal | Neuroscience and Biobehavioral Reviews |
| Volume | 35 |
| Issue number | 9 |
| DOIs | |
| State | Published - Oct 2011 |
Funding
Personal note from JRM: Jaak Panksepp has played a much larger and more vital role in the evolution of the research and program development than reflected in this manuscript. He has been a mentor and a friend, an enthusiastic supporter and critical thinker, and a remarkably sharing individual-both in terms of his time, his ideas and willingness to help. I have been significantly influenced by Jaak since my graduate school days in biochemistry starting in the 1970s when I would make the trek to Bowling Green State University for the privilege and pleasure of spending free weekends working with Jaak. His influence was instrumental in helping me craft a Ph.D. in chemistry into a life's work trying to identify and connect molecular mechanisms to human behavior. When the opportunity to create the Falk Center for Molecular Therapeutics arose, the time had finally come to put all of this together and Jaak enthusiastically and most graciously agreed to be our Director of Affective Neuroscience and thus continue to significantly influence and shape our thinking. Today we seem to have actually done what we could only dream about 30 years ago, create novel potential therapeutics for treating a variety of CNS disorders including depression, anxiety and perhaps even make an impact on autism spectrum disorder. It has been a remarkable journey and now it appears that the real work is now beginning. This research was supported by the Hope for Depression Research Foundation, New York, NY (JSB, JB, JP and JRM), and The Dr. Ralph and Marian Falk Medical Research Trust, Chicago IL (JRM). We thank Mary Schmidt for her expert technical assistance, and the Northwestern University Behavioral Phenotyping Core for its assistance.
Keywords
- Autism
- GLYX-13
- Microarray
- NMDA
- Rats
- Rough-and-tumble play
- Vocalizations
ASJC Scopus subject areas
- Neuropsychology and Physiological Psychology
- Cognitive Neuroscience
- Behavioral Neuroscience