Published July 28, 2015
Scientists at the University at Buffalo School of Medicine and Biomedical Sciences have identified the mechanisms behind a genetic mutation that produces certain autistic behaviors in mice, as well as therapeutic strategies to restore normal behaviors.
The study describes the cellular and molecular basis behind some autistic behaviors; it also suggests potential biomarkers and pharmaceutical targets.
The research, published in Cell Reports, focuses on the loss of a gene called Shank3, an important risk factor for autism spectrum disorders (ASD). The researchers traced how this risk factor disrupts communication between neurons, leading to social deficits in mice.
They found that they are able to reverse these neuronal disruptions, restoring normal behavior in mice.
Mice with a Shank3 deficiency exhibited “drastically reduced” interest in social stimuli versus inanimate objects, suggesting “severe social deficits.” They also spent significantly more time in repetitive self-grooming than normal mice.
Previous studies have shown 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.
The Shank3 deficiency plays a key role in how neurons communicate. It has a significant effect on the activation of the NMDA (n-methyl-D-aspartate) receptor, which is critical to learning and memory.
Yan explained that the Shank3 deficiency disrupts the trafficking of this receptor and its function at critical transmission sites in the brain.
That disruption results from the dysregulation of actin filaments, which act as a kind of “highway” at synapses of the excitatory neurons 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,” said Yan.
“Actin filaments are very dynamic structures that are constantly being assembled and disassembled, processes controlled by numerous regulators,” Yan explained.
When the equilibrium of actin filament assembly is disrupted, 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,” said Yan.
“This upsets the equilibrium of actin filament assembly, which, in turn, disrupts the normal delivery and maintenance of NMDA and other critical receptors.”
The result is a significant effect on the functional plasticity of the synapse, which leads to the manifestation of some autistic behaviors.
The researchers found they were able to restore 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.
Yan’s co-authors in the Department of Physiology and Biophysics are:
Other co-authors are researchers from the Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai.