Neurotransmitter receptor architecture links local neurochemistry to semantic memory

Abstract

A fundamental challenge in neuroscience is understanding how the molecular and neurochemical architecture of the human cortex gives rise to sophisticated higher cognitive functions. The anterior temporal lobe (ATL) is a key hub for semantic memory, and its underlying GABAergic and glutamatergic neurochemistry supports semantic memory performance. However, the molecular receptor architecture underlying these neurochemical-cognitive relationships remains unknown. Here, we combined imaging transcriptomics and in vivo magnetic resonance spectroscopy (MRS) to investigate how neurotransmitter receptor organisation relates to local neurochemistry and semantic memory in the human ATL. We found that the ATL exhibited a distinct transcriptomically inferred receptor-subunit profile relative to control cortical regions (occipital cortex and vertex). Individual-specific spatial estimates of receptor-subunit gene expression were systematically associated with local GABA+ and Glx concentrations, revealing preferential coupling between GABAergic receptor genes and GABA+ and between glutamatergic receptor genes and Glx, alongside widespread cross-system associations between GABAergic receptor architecture and Glx. ATL GABA+ and Glx concentrations were positively associated with semantic memory performance, and GABAergic and glutamatergic receptor-subunit expression showed selective relationships with semantic memory accuracy. Crucially, mediation analyses revealed that GABA+ mediated associations between GABAergic receptor architecture and semantic performance, whereas Glx mediated both glutamatergic and widespread GABAergic receptor associations. Together, these findings reveal a coupled molecular-neurochemical architecture of the human ATL, linking neurotransmitter receptor organisation to regional neurochemical state and individual differences in semantic memory. Our findings provide a multiscale account of how cortical molecular organisation is associated with human higher cognitive function.