JAMA Psychiatry: Regional Specificity of Cortical Layer 3 Dendritic Spine Deficits in Schizophrenia
Schizophrenia is frequently associated with functional impairments including deficits in cognition and social interactions. These impairments are thought to emerge from dysfunction in the processing of information across distributed cortical circuits, including the primary visual cortex, the posterior parietal cortex, and dorsolateral prefrontal cortex. Communication across these regions relies on excitatory synapses located on dendritic spines of layer 3 pyramidal neurons.
Investigators at the University of Pittsburgh including Kenneth Fish, PhD (Associate Professor of Psychiatry), Robert Sweet, MD (UPMC Endowed Professor in Psychiatric Neuroscience and Professor of Psychiatry and Neurology), Matthew MacDonald, PhD (Associate Professor of Psychiatry), and David Lewis, MD (Distinguished Professor of Psychiatry and Neuroscience), conducted a case-control study examining postmortem brain tissue from 20 individuals with schizophrenia and 20 matched unaffected comparison individuals. The study tested whether dendritic spine density and spine size alterations differ across nodes of the cortical visual-spatial working memory network in schizophrenia.
In a paper published in JAMA Psychiatry, the researchers found marked regional specificity in dendritic spine alterations. Individuals with schizophrenia showed lower densities of small dendritic spines in primary visual cortex, whereas reductions in posterior parietal and dorsolateral prefrontal cortices were concentrated in medium and large spines—those thought to support stable, recurrent network activity.
“These findings suggest that schizophrenia does not affect cortical circuits uniformly. Instead, the illness appears to disrupt different types of synaptic connections in sensory versus association regions, which may help explain how both perceptual processing and higher-order cognitive functions are impaired,” said Dr. Fish, the study’s lead author.
Regional Specificity of Cortical Layer 3 Dendritic Spine Deficits in Schizophrenia
Fish KN, Sweet RA, MacDonald ML, Lewis DA.
JAMA Psychiatry. 2025;82(11):1123–1132. doi:10.1001/jamapsychiatry.2025.2221