Interneuron marker distributions consistent across humans and nonhuman primates are correlated with cortical signal amplitude and genetic risk for schizophrenia in the general population. Furthermore, they may explain regional differences in heritable brain function, according to study data published in Nature Communications.

Interneurons account for 20% to 30% of cortical neurons and develop stereotyped connections with excitatory projection neurons. Most interneurons express certain genetic markers such as somatostatin (SST), parvalbumin (PVALB), or vasoactive-intestinal peptide (VIP). Whereas SST interneurons target dendrites of the cortical projection neurons to regulate their input, PVALB interneurons synapse on periosomatic regions and regulate output.

Increased density of SST interneurons may filter noisy or irrelevant cortical signals and stimulate cognition necessary for higher order thought, while increases in PVALB interneurons may produce stronger feedback inhibition on excitatory neurons and may be suited to processing constantly changing sensorimotor stimuli. Spatial distributions of interneuron subtypes may underlie regional signaling differences across the cortical sheet.

Kevin M. Anderson, a PhD candidate at the department of psychology, Yale University, New Haven, Connecticut, and colleagues used publicly available human gene expression data from 6 postmortem donors and analyzed gene expression data from the Allen Human Brain Atlas and the NIH Blueprint Non-Human Primate Atlas. They relied on in-vivo imaging and genetic analyses of aging white individuals in the United Kingdom.

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The investigators found a negative spatial relationship between SST and PVALB in both human and primate samples, suggesting that interneuron marker gradients may reflect an essential organizational characteristic of the primate cortex. SST interneurons were densest within the medial prefrontal cortex, anterior insula, and temporal poles. In contrast, PVALB interneurons were most prevalent within the visual, motor, and dorsal parietal cortex. The negative correlation between distribution of SST and PVALB was also found in subcortical regions, including the hypothalamus, globus pallidus, amygdala, and thalamus, but not the hippocampus, ventral tegmentum/substantia nigra, and the striatum.

Data from animal models and postmortem tissue analysis indicate that interneuron dysfunction is an essential feature of schizophrenia. To determine if interneuron-related genetic variation is linked to risk of the disease, the investigators tested whether polygenic risk for schizophrenia is greater among single nucleotide polymorphism variants, namely PVALBSNP and SSTSNP, relative to the rest of the genome. They observed significant increases in schizophrenia polygenic risk for PVALBSNP, but not for SSTSNP.

The researchers noted that “schizophrenia is one of the most heritable forms of psychiatric illnesses, with converging lines of evidence pointing toward GABAergic and parvalbumin interneuron abnormalities as cardinal features of the disorder.” Abnormalities in PVALB interneurons are believed to underlie disorder-related disruption of gamma band oscillations and working memory.

Limitations included the use of single molecular markers to infer the relative presence of SST and PVALB interneurons, the use of guilt by association logic to nominate interneuron related gene sets, and the use of a heterogeneous population for in-vivo imaging and genetic analyses.

The researchers concluded, “Integrating genetic, transcriptional, and neuroimaging data, we demonstrate that spatial distributions of interneurons are stereotyped across species and development, and explain a substantial portion of the heritable variation in RSFA [resting state signal amplitude], a measure of in-vivo brain activity.”


Anderson KM, Collins MA, Chin R, Ge T, Rosenberg MD, Holmes AJ. Transcriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk. Nature Communications. 2020.