Systems-Level Transcriptomic and Cellular Architecture of the Human Striatum in Schizophrenia and Bipolar Psychosis

Abstract

Psychosis involves striatal circuit dysfunction, but the regional molecular and cellular changes remain unclear. We re-analyzed 215 postmortem RNA-seq samples (72 donors: 36 controls, 28 schizophrenia, 8 bipolar disorder with psychosis) from the nucleus accumbens, caudate and putamen, asking whether diagnosis-associated transcriptional changes are region-specific and whether they reflect cellular composition or cell-intrinsic state. Region-specific limma-voom models identified 0, 141 and 2152 schizophrenia-associated genes (FDR < 0.10) in the nucleus accumbens, caudate and putamen; the small bipolar-psychosis group yielded one gene, with limited power to detect additional associations. Correlation-aware camera tests supported immune–inflammatory Hallmark programs in the caudate and putamen, whereas nucleus accumbens signals were not robust to sequencing-run adjustment. Leukocyte-reference deconvolution was uninformative for brain parenchyma. Across four deconvolution estimators and two single-nucleus references, including an independent eight-donor striatal reference, putamen samples from donors with schizophrenia showed a consistently lower oligodendrocyte-lineage reference weight, whereas attribution to oligodendrocyte precursor cells specifically was method-dependent. Exploratory directional signatures (dopamine–adenosine, glutamate–calcium, Activin–SMAD, APP processing) remained supported in the caudate and putamen after direction-selection permutation conditional on fixed gene membership and were driven mainly by schizophrenia. The results characterize a dorsal–striatal, schizophrenia-associated transcriptional and oligodendroglial signal and provide prioritized hypotheses for independent validation.