NLRP1 inflammasome activation in schizophrenia

Aims: In the context of the maternal immune activation and neuroinflammation hypotheses of schizophrenia (SZ), we studied NLRP1 mRNA and protein expression in the postmortem brain tissue from a total of 10 SZ and 10 controls. Methods: RNA underwent reverse transcription and was hybridized onto the Affymetrix HG-U133 Plus 2.0 array, using the same protocol as the GeneChip Human Exon 1.0ST Arrays (Affymetrix, Santa Clara, CA, USA), which examines over a million exons, spanning 17,868 NCBI RefSeq transcripts. Brain tissue samples were embedded in paraffin, cut into 12 μm-thin sections, and subjected to immunohistochemical staining using NLRP1 monoclonal antibody (Abcam, Cambridge, UK, AB_776633). Results: In the medial orbitofrontal cortex (MOFC, Brodmann’s area 11/12) and dorsolateral prefrontal cortex (BA 46) from both hemispheres of 6 SZ subjects, the NLRP1 mRNA expression was significantly higher than in 6 controls (p < 0.05). Given the highest expression difference in the right hemisphere’s MOFC, we assessed NLRP1-immunoreactive pyramidal neurons in layers III, V, and VI in the MOFC of the right hemisphere of 7 SZ and 5 control brains. Compared to controls, we observed a significantly higher number of NLRP1-positive pyramidal neurons in the SZ brains (p < 0.01), suggesting NLRP1 inflammasome activation in subjects with SZ. Conclusions: The dysfunction of layer III pyramidal neurons aligns with working memory deficits, while impairments of pyramidal neurons in layers V and VI likely disrupt predictive processing in subjects with SZ. Therefore, we propose NLRP1 inflammasome as a potential biomarker and therapeutic target in SZ.