Biological Psychiatry – Alterations in Prefrontal Cortical Somatostatin Neurons in Schizophrenia: Evidence for Weaker Inhibition of Pyramidal Neuron Dendrites
Cognitive dysfunction in schizophrenia, including impaired working memory, is associated with altered GABA (gamma-aminobutyric acid) signaling in the dorsolateral prefrontal cortex. Among GABA neurons, the somatostatin–expressing subtype appears to be especially affected because multiple postmortem studies have reported large somatostatin messenger RNA (mRNA) deficits in the dorsolateral prefrontal cortex of individuals with schizophrenia. These deficits reflect lower somatostatin mRNA expression per neuron rather than fewer somatostatin neurons, suggesting that somatostatin neurons are present but functionally altered in schizophrenia. However, little is known about the status of other properties of this GABA neuron subtype.
To improve our understanding of alterations in somatostatin subtype of GABA neurons, a team of investigators including Samuel Dienel, MD, PhD (Pitt MSTP student; currently psychiatry resident, Yale University); Kenneth Fish, PhD (Associate Professor of Psychiatry); and David Lewis, MD (Distinguished Professor of Psychiatry and Neuroscience), examined 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), the enzyme that synthesizes GABA, and somatostatin mNRA levels in individual somatostatin neurons in postmortem brain tissue from individuals with schizophrenia and from an unaffected comparison group.
In a paper published in Biological Psychiatry, the scientists reported strong and convergent evidence of lower GAD67 and somatostatin mRNA levels within somatostatin neurons in layers 2/superficial 3 of the dorsolateral prefrontal cortex in individuals with schizophrenia, and these findings were associated with a proxy measure of cognitive ability.
“Because the levels of both GABA and somatostatin influence the strength of synaptic inhibition, our findings suggest that the ability of somatostatin neurons to inhibit pyramidal neuron dendrites is lower in people with schizophrenia. Given that dendritic inhibition appears to be important for working memory, our findings implicit altered inhibition from somatostatin neurons in the cognitive dysfunction of schizophrenia,” said Dr. Lewis, senior and corresponding author of the study.
Alterations in Prefrontal Cortical Somatostatin Neurons in Schizophrenia: Evidence for Weaker Inhibition of Pyramidal Neuron Dendrites
Dienel SJ, Wade KL, Fish KN, Lewis DA
Biological Psychiatry, Volume 98, Issue 2, 2025, Pages 156-166, ISSN 0006-3223, https://doi.org/10.1016/j.biopsych.2025.01.010.