JAMA Psychiatry: Diagnostic Specificity and Association with Cognition of Molecular Alterations in Prefrontal Somatostatin Neurons in Schizophrenia

Individuals with schizophrenia exhibit pronounced deficits in somatostatin messenger RNA levels in the dorsolateral prefrontal cortex and other prefrontal regions. Lower somatostatin messenger RNA levels appear to be due to lower gene expression per neuron without a deficit in somatostatin-positive neuron density, suggesting that in schizophrenia, somatostatin neurons are functionally altered in the dorsolateral prefrontal cortex. Lower dorsolateral prefrontal cortex somatostatin messenger RNA levels have also been reported in bipolar disorder and major depressive disorder.

Molecularly distinct subtypes of somatostatin neurons in the superficial and deep zones of the dorsolateral prefrontal cortex may contribute to different functional processes mediated by this region. To improve our understanding of somatostatin alterations in schizophrenia across these zones, scientists from the University of Pittsburgh including Samuel Dienel, PhD (Medical Scientist Training Program student); Kevin Dowling (Medical Scientist Training Program student); Kenneth Fish, PhD (Associate Professor of Psychiatry); and David Lewis, MD (Distinguished Professor of Psychiatry and Neuroscience, Thomas Detre Professor of Academic Psychiatry), investigated the prefrontal cortical patterns of molecular alterations in somatostatin neurons with the goal of determining whether these patterns are diagnosis specific and whether they are associated with measures of premorbid cognitive function.

The investigators used laser microdissection and quantitative polymerase chain reaction or fluorescent in situ hybridization to examine messenger RNA levels in 200 postmortem brain tissue specimens. The specimens were previously obtained from individuals with schizophrenia, major depressive disorder, or bipolar disorder, as well as unaffected individuals from a community population. Demographic, clinical, and educational information was ascertained through psychological autopsies.

The findings from the study, recently published in JAMA Psychiatry, revealed that somatostatin neuron alterations were present in both superficial and deep prefrontal zones in individuals with schizophrenia, in only the superficial zone in individuals with major depression disorder, and in neither zone in individuals with bipolar disorder. In schizophrenia, alterations in the superficial zone were associated with measures of premorbid cognitive function.

“These findings, by providing a robust demonstration of the cell type and diagnostic specificity of somatostatin neuron molecular alterations in the dorsolateral prefrontal cortex, substantially advance our understanding of their contribution to the pathophysiology of schizophrenia,” said Dr. Lewis, the paper’s senior author. “In particular, they provide strong evidence supporting a role for somatostatin neuron alterations in the cognitive impairments of the illness.”

Diagnostic Specificity and Association with Cognition of Molecular Alterations in Prefrontal Somatostatin Neurons in Schizophrenia
Dienel SJ, Dowling KF, Barile Z, Bazmi HH, Liu A, Vespoli JC, Fish KN, Lewis DA.
JAMA Psychiatry. 2023;80(12):1235-1245. doi:10.1001/jamapsychiatry.2023.2972