Researchers have found that the protein encoded by a gene linked with cognition (thinking) responds to existing drug compounds. This discovery points to a possible route for treating certain cognitive deficits in illnesses including schizophrenia.

Published April 22nd in Neuron, the research was led by Paul F. Worley, M.D., recipient of a NARSAD 1997 Independent Investigator grant and a 2014 Distinguished Investigator grant. The scientific team included 2014 Young Investigator grantee Wenchi Zhang, Ph.D., and 2012 Young Investigator grantee Jing Wu, M.D. Drs. Worley, Zhang, and Wu are based at the Solomon H. Snyder Department of Neuroscience at Johns Hopkins University.

The team studied the Arc gene, which plays a role in different aspects of cognition. Deleting Arc weakens memory without disrupting processes needed for learning. But too much Arc activity can weaken the connections between neurons. Further, some proteins encoded by genes linked with schizophrenia interact with the Arc protein, suggesting a possible connection with the illness. For this study, the researchers looked at how Arc might produce its varied effects and how its activity might be limited by chemical compounds already approved by the Food and Drug Administration for clinical use.

The team found that Arc binds extensively with a protein called TARP gamma-2, important for signaling between neurons. When bound together, the two proteins may reduce activity at the brain’s AMPA receptors, critical in communicating signals between excitatory neurons throughout the brain.

The researchers also found that the antipsychotic medications thioridazine  and chlorpromazine––both of which are used to treat schizophrenia––reduced Arc binding to TARP gamma-2. This activity was unrelated to the mechanisms that drive the drugs’ antipsychotic effects. It suggests that Arc binding may be specifically targeted by antipsychotics or antipsychotic-type drugs but leaves open the question as to how. More work is needed, the researchers say, to determine exactly how Arc’s role in communication between neurons can be selectively targeted by drugs to treat cognitive deficits.



Read the abstract.