Summary: A new study identifies a potential drug target that may increase social interaction in some forms of autism spectrum disorder (ASD).
Source: University of Pennsylvania Perelman School of Medicine
Researchers at the Perelman School of Medicine, University of Pennsylvania, report a promising drug target that could improve social interaction in some forms of autism spectrum disorder (ASD). Their findings, published in Biological Psychiatry, use a new genetic mouse model to link a specific gene to altered amygdala circuitry and social behavior.
Current medications can treat associated symptoms of ASD—such as anxiety, depression, attention-deficit hyperactivity disorder, and irritability—but no drugs are approved specifically for the core social deficits of ASD. The neural and molecular causes of those social challenges remain poorly understood. “This research could significantly change our understanding of the causes and brain changes in autism and could lead to new treatment approaches for the harder-to-treat social aspects of ASD,” said Edward S. Brodkin, MD, associate professor of Psychiatry and director of the Adult Autism Spectrum Program at Penn.
Behavioral symptoms in ASD have been linked to atypical neuronal connectivity, but the molecular mechanisms behind altered brain physiology and social behavior are largely unknown. Human genetic studies have implicated Protocadherin 10 (PCDH10), a neural cell adhesion molecule, in ASD. PCDH10 helps guide brain development and maintain synapses—the connections where neurons communicate—and is highly expressed in specific brain regions, including the amygdala, which plays a central role in emotion, motivation, and social behavior.
To investigate PCDH10’s role, the team created mice that lack one copy of the Pcdh10 gene (Pcdh10+/-). Male Pcdh10+/- mice displayed reduced social approach behavior, resembling social withdrawal seen in people with ASD. This social deficit was more pronounced in males than females, echoing the higher prevalence of ASD in males. In the male mice, the researchers also found structural and functional abnormalities in amygdala circuits and reduced levels of certain NMDA-type glutamate receptor subunits in the amygdala.
Importantly, a brief treatment with d-cycloserine—a medication that binds the glycine site of the NMDA receptor and enhances glutamate signaling—restored normal social approach in the male Pcdh10+/- mice. “By enhancing NMDA-receptor signaling, the mice went from social avoidance to more typical social approach behavior,” Brodkin said. These preclinical results align with small initial clinical studies suggesting that d-cycloserine can improve social interaction in older adolescents and young adults with ASD, supporting further clinical investigation.
The mouse model provides a useful platform to explore why Pcdh10 haploinsufficiency preferentially affects males. Brodkin and collaborator Ted Abel, PhD, plan follow-up studies to map amygdala circuit dysfunction in greater detail and to uncover biological mechanisms that produce sex differences in social behavior. Those studies may reveal new molecular and circuit-level targets for treating social withdrawal in specific ASD subtypes.
About this research
The study identifies a direct link between reduced Pcdh10 expression, altered amygdala synaptic structure and function, and diminished social approach in male mice. It also shows that boosting NMDA-receptor signaling with d-cycloserine can reverse social deficits in this model, providing a rationale for further clinical exploration of NMDA-targeting strategies for social symptoms in ASD.
Co-authors: Hannah Schoch, Arati S. Kreibich, Sarah L. Ferri, Rachel S. White, Dominique Bohorquez, Anamika Banerjee, Russell G. Port, Holly C. Dow, Lucero Cordero, Ashley A. Pallathra, Hyong Kim, Hongzhe Li, Warren B. Bilker, Shinji Hirano, Robert T. Schultz, Karin Borgmann-Winter, Chang-Gyu Hahn, Dirk Feldmeyer, and Gregory C. Carlson.
Funding
This work was supported by the Pennsylvania Department of Health, the National Institutes of Health, The Sumitomo Foundation, The Takeda Science Foundation, Japan Society for the Promotion of Science (JSPS) KAKENHI, the Japanese Ministry of Education, Culture, Sports, Science and Technology, Deutsche Forschungsgemeinschaft International Research Training Group 1328, national training programs in behavioral and cognitive neuroscience and neurodevelopmental disabilities, the McMorris Autism Training Program, and an Autism Science Foundation predoctoral fellowship.
Source and original publication
Reported by Katherine Fenz, University of Pennsylvania Perelman School of Medicine. Original research: “Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene,” published in Biological Psychiatry, June 16, 2016. The study describes behavioral, synaptic, and circuit-level deficits in Pcdh10+/– mice and the rescue of social approach behavior with the NMDA partial agonist d-cycloserine.
Abstract
Background: Behavioral symptoms in autism spectrum disorder (ASD) have been linked to abnormal neuronal connectivity, but the molecular basis of these changes is not well understood. Human genetics implicates PCDH10, a nonclustered protocadherin, in ASD. PCDH10 expression is enriched in the basolateral amygdala—a region implicated in social deficits. Prior work indicates roles for Pcdh10 in axon outgrowth and glutamatergic synapse elimination, but its impact on social behavior and amygdala connectivity remained unknown. The authors hypothesized that reduced Pcdh10 expression would impair social approach and alter amygdala structure and function.
Methods: Mice lacking one copy of Pcdh10 (Pcdh10+/–) and wild-type littermates were tested for social approach and other behaviors. The lateral/basolateral amygdala was examined for dendritic spine number and shape, and circuit function was assessed using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was measured in postsynaptic density fractions from the amygdala.
Results: Male Pcdh10+/– mice show reduced social approach, impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Acute treatment with the NMDAR partial agonist d-cycloserine rescued social approach deficits in male Pcdh10+/– mice.
Conclusions: Male Pcdh10+/– mice exhibit synaptic and behavioral deficits that model aspects of ASD. These animals serve as a new genetic model to investigate neural circuit and behavioral alterations relevant to autism and point to NMDA-receptor signaling as a potential target for treating social dysfunction in certain ASD subtypes.