Neuroscientists of National Centre for Biological Sciences (NCBS) have identified synaptic defects in an area of the brain which causes debilitating emotional symptoms of Fragile X Syndrome (FXS), a leading genetic cause of autism and mental retardation.

The year-long research led by Prof Sumantra Chattarji, National Centre for Biological Sciences, Bangalore is now viewed to have potential therapeutic significance because it also shows that even a relatively brief pharmacological treatment is capable of correcting some of these defects in mice that were genetically engineered to model FXS.

The study was a collaborative effort between NCBS and New York University (NYU). The grants came in from multiple sources including FRAXA Research Foundation, National Institutes of Health, Pfizer Asia R&D Collaborative Grant and NCBS.

People with FXS, which is a mutation in a gene on the X chromosome, suffer from learning disabilities, attention deficit, seizures, anxiety and mood instability.

In order to assess the cellular and molecular basis for the emotional problems associated with FXS, neuroscientists from NCBS and NYU studied neurons and synapses in the amygdala, which is a small, almond-shaped part of the brain. The region is known to mediate emotion influence on memory which is affected in FXS model mice, said Dr Chattarji.

Using electrophysiological recordings from neurons in the amygdala, Aparna Suvrathan, a PhD student at Prof. Chattarji's lab in NCBS found that there were defects on both sides of synapses in the amygdala. The neurons were not properly communicating with each other.

Prof Eric Klann and his team at the NYU identified the molecular correlates of these defects, giving the researchers a firm understanding on the exact location of breakdown.

Together, these deficits impair the ability of neurons in the amygdala to communicate and encode information. "We looked at ways to normalize communication between neurons. The focus was on Group I metabotropic glutmate receptors (mGluRs), which has been implicated in synaptic dysfunction in other brain areas in FXS", explained Dr Chattarji.

The researchers found that some of the synaptic deficits could be reversed when the amygdala neurons in adult FXS model mice were treated with a drug that blocked the receptors. The functionality of receptors and certain aspects of normal communication between neurons could be restored.

The findings hold promise for addressing FXS which is a developmental disorder manifesting in early in childhood. The study has now shown that synaptic defects can be corrected pharmacologically even after the disease alters the brains of the FXS mice.

With this finding, Prof Chatarji's lab will now look if there is a specific window of opportunity to reverse the FXS effects and if the mGluR blockers would be effective irrespective of age. "We are open to collaborations with pharma companies to investigate these important issues, especially with newer and more potent compounds. For instance, we already have an ongoing collaboration with the Autism Unit at Pfizer, Groton, CT, USA," said Prof Chatarji.

Other research efforts include continuing studies of stress effects on the amygdala, which is the emotional hub of the brain. Another major focus of Prof Chatarji's lab research, is aimed at identifying cellular and molecular mechanisms of anxiety, depression and post-traumatic stress disorder for which its collaborations with Pfizer, USA and Servier, France are notable in this connection, he said.