It may be possible to boost social interaction in people with autism by using a new therapeutic drug target, University of Pennsylvania researchers say.
The researchers from Penn’s Perelman School of Medicine used mouse models of autism in order to examine the gene called Protocadherin 10 (PCDH10). The gene, as the researchers described in a press release, is a neural cell adhesion molecule involved in both brain development and maintenance of neural synapses. While there are medications available for people with autism to treat associated symptoms like anxiety, depression, attention deficit hyperactivity disorder (ADHD), and irritability, there is nothing currently approved for social interactions.
"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," senior author Edward S. Brodkin, MD, said in the statement.
The investigators deleted one of the two copies of PCDH10 from the mice, they showed decreased social approach behaviors. The researchers also noted that this habit was observed more often in males than females, which seemed consistent with understood behaviors of autism in humans. The mice with one deleted PCDH10 gene also showed differences in the structure and abilities of the amygdala, the researchers said.
In order to remedy the social behavioral deficits, the researchers administered d-cycloserine to the male mice to bind glycine to NMDA receptors and increase glutamate signaling at the receptors. "By enhancing NMDA receptor signaling, the mice went from social avoidance to more typical social approach behavior," Brodkin observed.
Again, the researchers said this finding was in line with what has been observed in small, preliminary clinical studies of human patients with autism. In these studies, d-cycloserine was seen to significantly boost social behaviors in older adolescents and young adults who were diagnosed with autism spectrum disorders. The researchers believe their findings can lend credibility to these small human studies and provide a kickstart for other investigators to continue this work in human patients.
In the future, Brodkin and his team plan to continue to use mice models of autism to understand why the presence or absence of PCDH10 seems to affect males more than females in terms of social behaviors. The researchers want to continue to learn more about these behaviors and how they are affected by the amygdala to point toward better future treatment approaches for social behaviors in certain autism spectrum disorder subtypes.
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Schoch H, Kreibich AS, Ferri SL, White RS, Bohorquez D, Banerjee A, Port RG, Dow HC, Cordero L, Pallathra AA, Kim H, Li H, Bilker WB, Hirano S, Schultz RT, Borgmann-Winter K, Hahn CG, Feldmeyer D, Carlson GC, Abel T, Brodkin ES. Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene. Biol Psychiatry. 2016 Jun 16. pii: S0006-3223(16)32474-X. doi: 10.1016/j.biopsych.2016.06.008. [Epub ahead of print]
Behavioral symptoms in individuals with autism spectrum disorder (ASD) have been attributed to abnormal neuronal connectivity, but the molecular bases of these behavioral and brain phenotypes are largely unknown. Human genetic studies have implicated PCDH10, a member of the δ2 subfamily of nonclustered protocadherin genes, in ASD. PCDH10 expression is enriched in the basolateral amygdala, a brain region implicated in the social deficits of ASD. Previous reports indicate that Pcdh10 plays a role in axon outgrowth and glutamatergic synapse elimination, but its roles in social behaviors and amygdala neuronal connectivity are unknown. We hypothesized that haploinsufficiency of Pcdh10 would reduce social approach behavior and alter the structure and function of amygdala circuits.
Mice lacking one copy of Pcdh10 (Pcdh10+/-) and wild-type littermates were assessed for social approach and other behaviors. The lateral/basolateral amygdala was assessed for dendritic spine number and morphology, and amygdala circuit function was studied using voltage-sensitive dye imaging. Expression of Pcdh10 and N-methyl-D-aspartate receptor (NMDAR) subunits was assessed in postsynaptic density fractions of the amygdala.
Male Pcdh10+/- mice have reduced social approach behavior, as well as impaired gamma synchronization, abnormal spine morphology, and reduced levels of NMDAR subunits in the amygdala. Social approach deficits in Pcdh10+/- male mice were rescued with acute treatment with the NMDAR partial agonist d-cycloserine.
Our studies reveal that male Pcdh10+/- mice have synaptic and behavioral deficits, and establish Pcdh10+/- mice as a novel genetic model for investigating neural circuitry and behavioral changes relevant to ASD.