Molecular alterations in chondrolectin-containing somatostatin neurons in schizophrenia differ based on circuit...

Alterations in cortical somatostatin (SST)-containing GABAergic interneurons are among the most consistently replicated molecular findings in schizophrenia. Whether these alterations primarily reflect intrinsic cellular vulnerabilities, regional circuit context, or an interaction between the two remains unclear. To address this question, we examined a transcriptionally distinct SST neuron subtype that selectively expresses chondrolectin (CHODL), referred to as CHODL-SST neurons, across two brain regions with markedly different circuit organization: deep layer 6 and adjacent subcortical white matter of the dorsolateral prefrontal cortex (DLPFC) and the caudate nucleus.Using multiplex fluorescent in situ hybridization in postmortem tissue from 18 matched pairs of schizophrenia and unaffected comparison individuals, we quantified mRNA levels of CHODL, SST, neuropeptide Y (NPY), and nitric oxide synthase (NOS1) within CHODL-SST neurons in both regions.In the DLPFC, CHODL-SST neurons exhibited lower mRNA levels for all four transcripts in schizophrenia, with small-to-medium effect sizes (-0.29 to -0.52). In contrast, effect sizes in the caudate were nominal (-0.13 to 0.03), with Bayesian analyses providing strong evidence for no difference in schizophrenia. For every transcript, a significant diagnosis-by-region interaction (all p < 0.005) highlighted a striking dissociation between cortical and striatal CHODL-SST neurons.These findings indicate that schizophrenia-associated molecular alterations in CHODL-SST neurons are regionally selective and preferentially affect cortical populations. Rather than reflecting uniform cell-intrinsic vulnerability, these results support a model in which differential vulnerability emerges from the interaction between subtype-specific molecular features and regional circuit context, with implications for understanding SST neuron dysfunction and developing circuit-informed therapeutic strategies.