Cell Density and mRNA Expression of Inhibitory Interneurons in Schizophrenia: A Meta-Analysis

Importance

GABAergic inhibitory interneurons have been implicated in the pathophysiology of schizophrenia. However, there is conflicting evidence regarding the nature and extent of the deficits across brain areas and interneuron subtypes.

Objective

The primary objective was to determine the extent of changes in parvalbumin, somatostatin, calbindin, and calretinin interneurons across brain regions and cortical layers in schizophrenia compared to healthy controls. The secondary objective was to examine differences in neuronal density and neuronal mRNA expression of GABAergic interneurons.

Data Sources

A comprehensive search was conducted from Fall 2024 to Spring 2025, including terms related to schizophrenia, interneurons, immunohistochemistry and mRNA. Only post-mortem human studies containing neuroanatomical data of parvalbumin, somatostatin, calbindin, and calretinin interneurons were considered.

Study Selection

We selected immunohistochemistry and mRNA studies that examined parvalbumin, somatostatin, calbindin, and calretinin interneuron density or expression in schizophrenia patients.

Data Extraction and Synthesis

Data were extracted following PRISMA guidelines and were pooled with a random-effects model. A t-score statistic was applied to obtain distributions of effects. A two-sample t-test and Cohen’s effect size was used to compare across areas, layers, cell types and methods.

Main Outcome(s) and Measure(s)

Primary measurements/outcome were laminar interneuron density (assessed by immunohistochemistry) and gene expression (assessed by mRNA).

Results

Data from 28 immunohistochemistry studies (362 control participants, 335 individuals with schizophrenia) revealed that the hippocampus and prefrontal cortex were most consistently characterized by alterations in GABAergic interneurons; parvalbumin and somatostatin interneuron density was reduced in the hippocampus, while data from 18 mRNA studies (524 control participants, 519 individuals with schizophrenia) indicated reduced parvalbumin and somatostatin expression in prefrontal cortex. Layer-specific analysis demonstrated that parvalbumin interneurons were most affected in the superficial layers of prefrontal cortex, while somatostatin interneurons exhibited the strongest deficits in layers 2 and 5.

Conclusions and Relevance

Our results show that GABAergic interneurons in the PFC and hippocampus are particularly affected. Parvalbumin and somatostatin showed the largest deficits, involving superficial layers and layer 5. We also identified significant reductions in parvalbumin and calretinin interneuron density in subcortical areas. Together, these data have important implications for the pathophysiology and computational models of circuits deficits in the disorder.

KEY POINTS