Inflammation-associated alterations in mGluR transcript expression in the human nucleus accumbens independent of schizophrenia diagnosis

Metabotropic glutamate receptors (mGluRs) are of increasing interest in the pathophysiology and treatment of schizophrenia. In the nucleus accumbens (NAc), presynaptic mGluRs (largely group II and III) can regulate the activity of medium spiny neurons (MSNs) through control of glutamate release from extra-striatal regions. Given that inflammatory pathways can modulate glutamate and dopamine signalling, inflammation may influence these mGluR-mediated mechanisms in schizophrenia. Cellular expression of mGluR mRNAs in the NAc was investigated using a publicly available single-nucleus RNA sequencing dataset. Frozen NAc tissue from individuals with schizophrenia (n = 30) and controls (n = 30) were obtained from the New South Wales Brain Tissue Resource Centre. Protein levels of glutamate receptors, mGluR2, mGluR3, mGluR4, mGluR7, and a dopamine synthesis enzyme, tyrosine hydroxylase (TH) were quantified by western blot. mGluR transcripts were measured using qRT-PCR. Neuroinflammatory status was determined from levels of pro-inflammatory transcripts (SERPINA3, IL6, IL1β, and TNFα). TH protein levels were elevated in the NAc of individuals with schizophrenia. GRM1 , GRM3 , GRM4 , GRM7 and GRM8 transcripts were strongly expressed in MSNs and inhibitory neurons. Gene and protein expression of the mGluRs did not differ between schizophrenia and controls. When the cohort was stratified into a high (n = 13) and a low (n = 42) inflammation group, GRM1 and GRM5 mRNAs were decreased in those with high inflammation. These data indicate that elevated inflammation, irrespective of schizophrenia diagnosis, is associated with a selective reduction of group I mGluR transcripts in the NAc. This suggests that inflammation may be a key modulator of glutamatergic signalling in this region.