Neuroreceptor loss linked to schizophrenia and autism

Experimental mice born without a particular neuroreceptor developed compulsive, antisocial behaviors similar to schizophrenia and autism in humans, according to a study published August 11, 2015 in Molecular Psychiatry.

The receptor, metabotropic glutamate receptor 5 (mGluR5), and its functions in the brain have been well studied. But the receptor’s role in parvalbumin-positive interneurons, which appears to be important in cognitive function, has never been investigated.

“We found that without this receptor in the parvalbumin cells, mice have many serious behavioral deficits,” said Terrence Sejnowski, PhD, head of the Computational Neurobiology Laboratory at the Salk Institute for Biological Studies, in La Jolla, CA. “And a lot of them really mimic closely what we see in schizophrenia.”

Previous research has shown that when molecular signaling is disrupted in parvalbumin cells during neurodevelopment, neural networks do not form correctly. In separate studies, mGluR5 receptors have been linked to addiction disorders, anxiety, and fragile X syndrome. But, in those cases, mGluR5 was affected in excitatory cells, not inhibitory cells like parvalbumin-positive interneurons.

Because these parvalbumin cells appear important in brain development, the researchers at the Salk Institute wondered what role mGluR5 plays. They partnered with Athina Markou, PhD, and her colleagues in the Department of Psychiatry at the University of California San Diego to develop mice in which mGluR5 was postnatally deleted from parvalbumin-positive interneurons.

Without the mGluR5 receptor in the parvalbumin cells, these mice had reduced numbers of parvalbumin-positive neurons and fewer inhibitory connections, as well as alterations in brain activity. This resulted in a number of neurodevelopmental problems, including obsessive, repetitive grooming behavior and antisocial tendencies. Also, the patterns of brain activity resembled those seen in humans with schizophrenia.

“This discovery implies that changes after birth, not just before birth, are affecting the way the network is set up,” said corresponding author Margarita Behrens, PhD, Salk staff scientist.

The results suggest that an alteration in mGluR5 receptors in these brain cells may be a critical step in the formation of some neurodevelopmental disorders, Dr. Sejnowski said. That’s good news, he added, because the molecular change is potentially reversible.

“The cells are still alive, and if we can figure out how to go in and change some of these molecular switches, we might actually be able to put the cells back into healthy, functioning states,” he said.

Dr. Behrens added that the study also should serve as a warning to the pharmaceutical industry to be cautious when developing drugs that affect mGluR5 throughout the whole brain. “There are a lot of clinical trials ongoing looking at modulating mGluR5 for anxiety and fragile X syndrome,” she said. “But our results suggest that if you affect parvalbumin neurons, you might get behavioral changes you weren’t expecting.”

Further research is needed to show whether the mGluR5 receptors in parvalbumin-positive interneurons are linked to neurodevelopmental disease in humans, the investigators noted.