Local co-expression of GLP1R and INS in human cortical interneurons

Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP1R) and insulin (INS), traditionally associated with peripheral metabolic regulation, also exert key functions in the central nervous system. We hypothesised that specific human cortical interneuron subtypes locally express GLP1R and INS, a molecular feature that may be relevant for exploring potential intracortical metabolic signalling mechanisms.

We analysed single layer 1 GABAergic interneurons microdissected from human cortical tissue using laser capture microdissection. Transcriptomic subtype identification was performed using digital PCR preamplification of LAMP5, SV2C and PRSS12 markers. GLP1R and INS and mRNA copy numbers were quantified using single-cell digital PCR, and spatial expression patterns were validated using RNAscope Hi-Plex in situ hybridisation.

Neurogliaform (LAMP5+, SV2C+, PRSS12-) and rosehip cells (LAMP5+, SV2C+, PRSS12+) exhibited significantly higher GLP1R and INS expression than other LAMP5 interneurons. GLP1R mRNA was found in 44/72 neurogliaform and 18/36 rosehip cells, whereas INS mRNA was detected in 29/72 and 11/36 respectively. No INS expression was detected in other LAMP5 interneurons. Co-expression analysis revealed significant statistical dependency (mutual information = 0.244, p<0.0001), indicating non-random co-expression.

Human cortical neurogliaform and rosehip interneurons selectively co-express GLP1R and INS, conceptualising the existence of a local intracortical GLP1R- insulin-signalling loop. These findings provide a context for future investigations into cerebral glucose-regulatory processes implicated in certain neurodegenerative conditions, such as mild cognitive impairment in diabetes mellitus.