Transcriptional Map Identifies 37 Interneuron Subtypes in Human Prefrontal Cortex

Cognitive impairment in schizophrenia is increasingly linked to the disruption of inhibitory microcircuits within the dorsolateral prefrontal cortex, a region essential for executive function and working memory [1]. These deficits involve a significant loss of synaptic integrity, including a reduction in synaptophysin within the frontal cortex (effect size: -0.36, p = 0.04), and reduced expression of parvalbumin, a calcium-binding protein essential for the fast-spiking activity that synchronizes cortical networks [2, 3]. Recent evidence suggests these cellular changes are driven by the degradation of perineuronal nets (specialized extracellular matrices that stabilize inhibitory synapses and protect them from oxidative stress) and mitochondrial dysfunction, specifically elevations in the matrix protein cyclophilin D within parvalbumin-expressing interneurons of cortical layers 2-4 [4, 5]. While broad classes of interneurons are affected, the high degree of cellular diversity within these populations has complicated the development of targeted therapies [6]. A recent analysis of the human dorsolateral prefrontal cortex used single-nucleus RNA sequencing (a method to profile gene expression in individual cell nuclei) to identify 37 distinct interneuron subtypes, including nine parvalbumin and 11 somatostatin variants, providing a high-resolution transcriptional map to clarify their roles in cortical function [7].