Investigators at the Salk Institute have blazed a new trail branching out from the closely studied mGluR5 pathway in the brain, and they say it could ultimately lead to new therapies to treat neurodevelopmental disorders like autism and schizophrenia.
The mGluR pathway is well known in neurological disease research circles. Last fall Roche ($RHHBY) had to abandon an mGluR5 drug after it failed for closely related cases of Fragile X. And that was the same therapeutic approach taken by Seaside and Novartis ($NVS), which also failed. But at Salk, scientists say they were able to make new observations about mGluR5 that could radically alter the way new drugs are being developed, while adding that some of the old assumptions may be dangerously off base.
Until now, says the Salk team, no one has explored the role of mGluR5 receptors on a cell type known as parvalbumin-positive interneurons, which plays a role in cognition and oscillatory brain waves.
"We found that without this receptor in the parvalbumin cells, mice have many serious behavioral deficits," says Terrence Sejnowski, head of Salk's Computational Neurobiology Laboratory, which led the research published in Molecular Psychiatry on August 11, 2015. "And a lot of them really mimic closely what we see in schizophrenia."
A disruption of molecular signaling here scrambles brain networks. In the earlier work, says Salk, problems with glutamate signaling related to excitatory cells were linked with anxiety and Fragile X. Switching to inhibitory cells like the parvalbumin-positive interneurons, they found that deleting the receptor in mice triggered a host of symptoms associated with neurological disorders.
Margarita Behrens, corresponding author and Salk staff scientist, says that it appears that changes after birth are involved. New therapies that correct this flaw, the group adds, could make it possible to address these diseases. And they add a cautionary note for scientists who are hard at work on other drugs that involve the mGluR5 pathway.
"There are a lot of clinical trials ongoing looking at modulating mGluR5 for anxiety and Fragile X Syndrome," she says. "But our results suggest that if you affect parvalbumin neurons, you might get behavioral changes you weren't expecting."