Researchers find mutation responsible for altered brain function linked to autism

Mutations associated with autism that were previously thought to reduce excitatory synaptic transmissions are now shown to enhance those same transmissions, and result in autism-like behaviours in animal models, according to new research from Dr. Ann Marie Craig (pictured right) and colleagues at the Djavad Mowafaghian Centre for Brain Health. The team's findings suggest a link between elevated excitatory transmissions along some neural pathways and an increased risk of autism.

The study, published today in the journal Neuronfound that mice with the MDGA2 mutation demonstrated social and repetitive behaviors similar to symptoms of autism, as well as impaired spatial learning and memory. Led by Dr. Steven Connor, a joint postdoctoral fellow in the labs of Dr. Craig and Dr. Yu Tian Wang, the investigators found increases in spontaneous cortical activity and intracortical functional connectivity using imaging which, together with electrical recording data, suggests that the mutation is responsible for an imbalance in neurotransmission resulting in altered cortical processing.

The team’s discovery supports the possibility that there may not be a one-size-fits all approach to treatment for symptoms of autism spectrum disorders, and that potential therapies may need to be tailored to an individual’s genome.  

“Dr. Connor's finding of altered synaptic plasticity, showing enhancement of a cellular model of short term memory but a deficit in a model of long term memory in MDGA2 mutants, is quite unusual and warrants further investigation,” says Dr. Craig. “Identifying the mechanism by which the gene acts through altered neuroligin-neurexin signalling provides insight into potential therapeutic targets.”

The discovery is the result of intense collaboration between Dr. Craig’s lab and Dr. Yu Tian Wang and Dr. Tim Murphy, as well as Dr. Tohru Yamamoto’s lab at Kagawa University. Working together, the team brought unique perspectives in gene function and effects of mutation on brain structure, biochemical composition, electrophysiological signaling, regional activity, and behavior. Dr. Allen Chan, a joint postdoctoral fellow in the labs of Dr. Murphy and Dr. Wang, provided crucial imaging expertise.

“Dr. Chan's in vivo functional imaging was particularly important to facilitate comparison of this animal model with human fMRI studies in autism,” says Dr. Craig. “Such wide-field high-resolution imaging has rarely been performed on  genetic models of autism and will be key to better understanding disease etiology, identify biomarkers, and eventually develop individualized treatments.”  

“Our discovery forms the basis of a novel way about thinking about neuroligin-neurexin signaling,” says Dr. Connor. “We’ve shown that molecular regulators governing the interaction along neural pathways are important in understanding how autistic behaviours manifest in the brain.” 

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