Shank3 and hypersensitivity

Neuroscientists at MIT and Brown have found that mice lacking the protein Shank3, which has previously been linked with autism, were more sensitive to touch on their whiskers than genetically normal mice. Shank3-deficient mice also had overactive excitatory neurons in a region of the brain called the somatosensory cortex, which researchers believe accounts for their over-reactivity.

For this new study, headed by Dr. Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT and a member of MIT’s McGovern Institute for Brain Research, and Dr. Christopher Moore, a professor of neuroscience at Brown University, the team developed a way to measure the mice’s sensitivity to slight deflections of their whiskers, and then trained the mutant Shank3 mice and normal, wild-type mice to display behaviors that signaled when they felt a touch to their whiskers.

Through this, they found that mice that were missing Shank3 accurately reported very slight deflections that were unable to be detected by the normal mice. Once it was established that the mutant mice experienced sensory hypersensitivity, the researchers set out to analyze the underlying neural activity. For this, they used an imaging technique that measures calcium levels in specific cell types, which can then be used to indicate neural activity.

The results showed that when the mice’s whiskers were touched, excitatory neurons in the somatosensory cortex were overactive, which was contrary to the expectation that without Shank3, synaptic activity should drop, leading researchers to hypothesize that the root of the problem was low levels of Shank3 in the inhibitory neurons that normally turn down the activity of excitatory neurons. This would diminish those inhibitory neurons’ activity and allow excitatory neurons to go unchecked, leading to sensory hypersensitivity.

To test this idea, the researchers genetically engineered mice so that they could turn off Shank3 expression exclusively in inhibitory neurons of the somatosensory cortex. As suspected, they found that in these mice, excitatory neurons were overactive, even though those neurons had normal levels of Shank3. These results suggest that reestablishing normal levels of neuron activity could reverse this kind of hypersensitivity.

The Shank3 protein is important for the function of synapses, connections that allow neurons to communicate with each other. In past studies, Feng has shown that mice lacking the Shank3 gene display many traits associated with autism, including avoidance of social interaction and compulsive, repetitive behavior.

“We hope our studies can point us to the right direction for the next generation of treatment development,” says Feng

There are currently no treatments for sensory hypersensitivity, but the researchers believe that uncovering the cellular basis of this sensitivity may help in the development of potential treatments. Many other studies in mice have linked defects in inhibitory neurons to neurological disorders, including Fragile X syndrome and Rett syndrome, as well as autism.

“Our study is one of several that provide a direct and causative link between inhibitory defects and sensory abnormality, in this model at least,” Feng notes. “It provides further evidence to support inhibitory neuron defects as one of the key mechanisms in models of autism spectrum disorders.”

Next, Feng plans to study the timing of when these impairments arise during an animal’s development, which could help to guide the development of possible treatments. There are existing drugs that can turn down excitatory neurons, but these drugs have a sedative effect if used throughout the brain, so more targeted treatments could be a better option.

“We don’t have a clear target yet, but we have a clear cellular phenomenon to help guide us,” he states. “We are still far away from developing a treatment, but we’re happy that we have identified defects that point in which direction we should go.”