Scientists reverse the social traits associated with autism in a mouse model

Research is underway in the area of ​​mutations and genetic changes as well as brain and neurological disorders, including Autism Spectrum Disorder (ASD), and a new study of autistic mouse models has shown a possible link between mutations or deletions of the SHANK3 gene and a rare gene. disorder called Phelan-McDermid syndrome and TSA.

The study conducted by MIT researchers, in collaboration with Chinese researchers, revealed that mice with the SHANK3 mutation showed traits of autism, including avoiding social interactions. The study titled "Anterior cingulate cortex dysfunction underlies social deficits Shank3 mutant mice "was published in the latest issue of the journal Nature Neuroscience.

SHANK3 (green) is expressed with a neural marker (NeuN) in the anterior cingulate cortex of the mouse. Image credit: Guoping Feng

The research team succeeded in producing mutations of the SHANK3 gene in mice and studying their characteristics similar to those of autism. They noted that this mutation also resulted in structural and functional abnormalities and alterations in the region of the anterior cingulate cortex (ACC) of the brain in mice. Guoping Feng, Professor James W. and Patricia T. Poitras at MIT, a researcher at the McGovern Institute of MIT, Principal Investigator at the Stanley Institute's Center for Psychiatric Research Stanley and lead author of the study, explained, "The Neurobiological Mechanisms social deficits are very complex. and involve many regions of the brain, even in a mouse model. These results add another piece of the puzzle to the mapping of the neural circuits responsible for this social deficit in ASD models. Feng and his team collaborated with Wenting Wang and Shengxi Wu at the Fourth Military Medical University of Xi'an, China, for this study.

The team created SHANK3 mutant mice in their lab and attempted to study brain regions badociated with autism. They write that more than one area of ​​the brain has already been badociated with autism and especially with impaired social interactions. This included the prefrontal cortex (PFC) and its projections in the brain, including the nucleus accumbens and habenula. However, these studies did not reveal a direct link between the avoidance of social interactions in SHANK3 mutant mice and PFC modifications. For this study, the team focused on the ACC region of the brain of mutant mice. In a normal human being and animals, the ACC region is known to play a role in social interactions as well as in cognitive functions, decision-making, cost-benefit badysis, and motivation.

Among mutant mice with SHANK3 deletions, the researchers noted both structural and functional alteration at synapses between neurons, particularly in the ACC region. The team noted that this disruption of ACC excitatory neurons was responsible for the disruption of neuron communication, particularly during social interactions and badociated behaviors. There was a marked reduction in social interactions noted, among those with SHANK3 deletions. They wrote that they noted: "… glutamatergic synapses in pyramidal neurons of the anterior cingulate cortex (ACC) exhibit structural and functional alterations in mice with a mutation in Shank3, a high confidence candidate ASD gene. "

In a next step, the team activated the ACC neurons and verified if this could restore social interactive behaviors in mice. To this end, they used optogenetic techniques as well as targeted specific drugs (including "a positive modulator of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor" ") To see if they could revive the excitatory neurons of the cell. ACC and correct social interactive behavior and avoidance. The results seemed promising, they write.

The authors concluded that their "findings provide direct evidence of the notion that CAC plays a role in the regulation of social behavior in mice and indicate that CAC dysfunction may be implicated in social deficiencies of ASD" .

Wenting Wang explained, "We then plan to explore areas of the brain downstream of ACC that modulate social behavior in normal mice and autism models. This will help us better understand the neural mechanisms of social behavior, as well as social deficits in neurodevelopmental disorders. "

This study was funded by the China Natural Science Foundation and the National Institute of Mental Health (NIMH), the Center for Research on Psychiatric Disorders of Poitras and the Hock Autism Research Center. E. Tan and K. Lisa Yang. at the McGovern Institute at MIT.

Related study

A recent study by Marco Pagani and colleagues at the Center for Neuroscience and Cognitive Systems in Italy showed that the suppression of the SHANK3 gene was badociated with a disruption of prefrontal connectivity. The study titled "The Suppression of the Shank3 Autism Risk Gene Disrupts Prefrontal Connectivity" was published on July 3, 2019 in the Journal of Neuroscience.

The authors concluded that "SHANK3 deficiency affects higher order socio-communicative functions," but the actual mechanism is not clear. The team used a high resolution functional and structural MRI in adult male mice with suppression of SHANK3 to show that there was reduced connectivity in the prefrontal regions of the brain. They noted that this suppression resulted in "reduced density of short-range cortical projections and reduced gray matter volume". They concluded, "A SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via deregulation of higher order cortical connectivity."