Phylogenetic divergence of GABA_B receptor signaling in neocortical networks over adult life

Nat Commun. 2025 May 6;16(1):4194. doi: 10.1038/s41467-025-59262-8.

ABSTRACT

Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. GABA_B receptor (GABA_BR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. But, how GABA_BRs contribute to circuit-level inhibition over the lifespan of rodents and humans is poorly understood. In this study, we quantitatively determined the functional contribution of GABA_BR signalling to pre- and postsynaptic domains in rat and human cortical principal cells. We find that postsynaptic GABA_BR differentially control pyramidal cell activity within the cortical column as a function of age in rodents, but minimally change over adult life in humans. Presynaptic GABA_BRs exert stronger inhibition in humans than rodents. Pre- and postsynaptic GABA_BRs contribute to co-ordination of local information processing in a layer- and species-dependent manner. Finally, we show that GABA_BR signalling is elevated in patients that have received the anti-seizure medication Levetiracetam. These data directly increase our knowledge of translationally relevant local circuit dynamics, with direct impact on understanding the role of GABA_BRs in the treatment of seizure disorders.

PMID:40328769 | DOI:10.1038/s41467-025-59262-8