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

Max A. Wilson, Anna Sumera, Lewis W. Taylor, Soraya Meftah, Robert I. McGeachan, Tamara Modebadze, B. Ashan P. Jayasekera, Christopher J. A. Cowie, Fiona E. N. LeBeau, Imran Liaquat, Claire S. Durrant, Paul M. Brennan and Sam A. Booker ()
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Max A. Wilson: University of Edinburgh
Anna Sumera: University of Edinburgh
Lewis W. Taylor: University of Edinburgh
Soraya Meftah: University of Edinburgh
Robert I. McGeachan: University of Edinburgh
Tamara Modebadze: Newcastle University
B. Ashan P. Jayasekera: Newcastle University
Christopher J. A. Cowie: Royal Victoria Infirmary
Fiona E. N. LeBeau: Newcastle University
Imran Liaquat: Royal Infirmary Edinburgh
Claire S. Durrant: University of Edinburgh
Paul M. Brennan: Royal Infirmary Edinburgh
Sam A. Booker: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. GABAB receptor (GABABR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. But, how GABABRs 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 GABABR signalling to pre- and postsynaptic domains in rat and human cortical principal cells. We find that postsynaptic GABABR 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 GABABRs exert stronger inhibition in humans than rodents. Pre- and postsynaptic GABABRs contribute to co-ordination of local information processing in a layer- and species-dependent manner. Finally, we show that GABABR 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 GABABRs in the treatment of seizure disorders.

Date: 2025
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DOI: 10.1038/s41467-025-59262-8

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