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

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.