Transcriptional evidence of reduced BDNF trophic signalling capacity in the post-mortem human midbrain of schizophrenia cases with high inflammation

Abstract

Elevated inflammation in the midbrain of ~ 45% of people with schizophrenia may relate to altered trophic support for neurons in schizophrenia. Dopamine neurons require trophic support from Brain-Derived Neurotrophic Factor (BDNF), that signals via the full-length Tropomyosin kinase B receptor (TrkB^TK+). The truncated BDNF receptor (TrkB^TK−) may perpetuate neuroinflammation and the apoptosis-related p75 receptor may counteract the effects of BDNF. We hypothesised that transcriptional changes in either BDNF, and/or a transcription factor critical for the maintenance of dopamine neurons (Nuclear Receptor Related-1 protein; NURR1), and/or BDNF receptors – TrkB (TK + or TK-) and p75, would be found in the post-mortem schizophrenia midbrain, particularly in high inflammation cases. Using RT-qPCR, mRNA levels of NURR1, BDNF, TrkB and p75 were quantified from schizophrenia (n = 65) and control (n = 64) ventral mesencephalon. We found significant decreases in BDNF IV, TrkB^TK+ and NURR1 (14–18%) and increases in TrkB^TK− and p75 (18–35%) mRNA levels in schizophrenia compared to controls (all p < 0.05), with exacerbation in high inflammation schizophrenia. To determine whether these changes result from chronic antipsychotic treatment, we treated healthy adult rats with antipsychotics and found all corresponding trophic mRNAs to be unaltered. SnRNAseq of human midbrain showed that p75 receptor mRNA is primarily localised in oligodendrocytes and pan-TrkB mRNA is distributed to both neurons and astrocytes. We confirmed that p75 was localised to oligodendrocyte-like cells by immunohistochemistry. Altogether, we find transcriptional evidence of reduced levels of trophic support in the midbrain in schizophrenia and suggest that this may directly impact dopamine neuron health, particularly in neuroinflammatory conditions.