The mechanisms underlying a genetic mutation that results in certain autistic behaviors in mice, as well as therapeutic strategies to restore normal behaviors, have been identified by scientists at the University at Buffalo.
The paper looks at the loss of a gene called Shank3, an important risk factor for autism spectrum disorders (ASD). The researchers, led by professor Zhen Yan, PhD, trace how this risk factor disrupts communication between neurons, leading to social deficits in mice.
And, in their most significant finding, they are able to reverse these neuronal disruptions, restoring normal behavior in mice.
Previous studies demonstrated that approximately 84 percent of people with a Shank3 deletion or loss-of-function mutation had an ASD. But just how this occurs has remained unknown.
Social Interest Drastically Reduced
The paper reports that mice with a Shank3 deficiency showed “drastically reduced” interest in social stimuli, i.e., other mice, versus inanimate objects, suggesting “severe social deficits.” They also spent significantly more time in repetitive self-grooming than normal mice.
The Shank3 deficiency plays a key role in how neurons communicate, the researchers found. It has an important effect on the activation of the NMDA (n-methyl-D-aspartate) receptor, which is critical to learning and memory.
The Shank3 deficiency disrupts the trafficking of this receptor, Yan explained, as well as it’s function at critical transmission sites in the brain. That disruption, they found, results from the dysregulation of actin filaments, which act as a kind of cellular “highway” in the brain’s prefrontal cortex, the command center for “high-level” executive functions and a key region implicated in ASD.
“This research is the first to show that, in animals, abnormal actin regulation causes autism-like behaviors. Actin filaments are very dynamic structures that are constantly being assembled and disassembled, processes controlled by numerous regulators.
When something upsets the equilibrium of actin filament assembly, key cellular functions fall apart.
With Shank3 deficiency, we have found that the expression or activity of some actin regulators, such as cofilin, is altered. This upsets the equilibrium of actin filament assembly, which, in turn, disrupts the normal delivery and maintenance of NMDA and other critical receptors.”
Synapse Functional Plasticity
The result is a very significant effect on the functional plasticity of the synapse, which, in turn, leads to the manifestation of some autistic behaviors.
Dramatically, researchers found they were able to reverse this process, restoring normal behaviors in the Shank3-deficient mice, once the activity of cofilin or other regulators was returned to normal. This, in turn, restored actin dynamics at cortical synapses, allowing for the normal trafficking and functioning of NMDA receptors.
“Once actin filaments and NMDA receptors returned to normal, we observed a robust and long-lasting rescue of the social interaction deficits and repetitive behavior in the Shank3-deficient mice,” said Yan. “Our results suggest a promising therapeutic strategy for treating autism.”
Lara J. Duffney, Ping Zhong, Jing Wei, Emmanuel Matas, Jia Cheng, Luye Qin, Kaijie Ma, David M. Dietz, Yuji Kajiwara, Joseph D. Buxbaum, Zhen Yan
Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators
Cell Reports DOI: http://dx.doi.org/10.1016/j.celrep.2015.04.064
Illustration: scanning electron micrograph, showing differentiating neurons grown in culture. Annie Cavanagh, Wellcome Images, Creative Commons by-nc-nd 4.0