April 21, 2014. In schizophrenia, neurons in the brain seem to shrivel. Postmortem studies find a shortage of the small, bulbous structures that typically dot the branches responsible for receiving messages from other neurons. These round “dendritic spines” appear to be excessively pruned back in schizophrenia. This would fragment the lines of communication between neurons and possibly lead to the troubles with thinking in the disorder.
A new study published April 3 in the Proceedings of the National Academy of Sciences suggests a way to stave off this spine loss, by way of an experimental drug for cancer. Researchers led by Akira Sawa at Johns Hopkins University, Baltimore, Maryland, found that compounds that block a class of proteins responsible for remodeling cell structures, called p-21 activated kinases (PAKs), could promote dendritic spines in rodent models of schizophrenia.
First author Akiko Hayashi-Takagi and colleagues studied rat neurons engineered to carry lower than normal levels of a protein encoded by disrupted in schizophrenia 1 (DISC1), a gene suspected in schizophrenia and other mental illnesses. Normally, electrical signals from other neurons bulk up spines, but in neurons deficient in DISC1, spines were stripped off the dendrites. However, treating the neurons with PAK inhibitors protected them from spine loss. Going several days with low levels of DISC1 also degrades spines, but PAK inhibitors could protect neurons from spine loss, and could also partially resuscitate spines after the excessive pruning.
In addition, PAK inhibitors promoted spines in living mice with decreased levels of DISC1 and partially reversed a behavioral abnormality found in them that has been linked to schizophrenia. Though much work remains to be done before PAK inhibitors are known for certain to work in people with schizophrenia, the findings suggest that remodeling the tiny structures of neurons may be a new therapeutic strategy for schizophrenia.