Sex-related perturbations in schizophrenia and bipolar disorder brains reflect microRNA-mediated cholinergic/neurokine interactions

Recent reports revealed massive overlaps between the molecular pathologies of schizophrenia (SCZ) and bipolar disorder (BD), but did not address the prominent clinical differences between men and women patients with these syndromes and the corresponding neurotransmitter and transcript regulators of their biological features. Here, we report sex-specific divergence of central cholinergic transcript networks in large patient brain datasets. Connectome analyses based on single cell- and small RNA-sequencing highlighted the gp130-family neurokine pathway controllers of immune functions, the LHX6 and LHX8 transcription factors that can drive neuronal cholinergic differentiation, the circadian regulators CLOCK and RORA, and the microRNA hsa-miR-125, -520, and -1275 families. Moreover, exposing the female humanoriginated LA-N-2 neuronal cells to the neurokine `ciliary neurotrophic factor` induced the transcriptional network surrounding acetylcholine (ACh) function, including the choline acetyltransferase (ChAT) and its intronic vesicular transporter (vAChT), the high affinity choline transporter (HACU, aka SLC5A7), muscarinic and nicotinic ACh receptors and the Ach hydrolyzing enzyme acetylcholinesterase (AChE), which we showed to be suppressed by miR-125b-5p. Independent patient datasets implicated miR-regulated cholinergic-neurokine interactions in SCZ and BD in the sex-related and circadian control of cholinergic neurons, opening new venues for seeking sex-related biomarkers and therapeutic targets, also in other transmitter systems and diseases.