Pre- and postsynaptic mechanisms of neuronal inhibition assessed through biochemically detailed modelling of GABAB receptor signalling

Mäki-Marttunen, T.; Kismul, J. F.; Pajo, K.; Schulz, J. M.; Manninen, T.; Einevoll, G. T.; Linne, M.-L.; Andreassen, O. A.; Kotaleski, J. H.

doi:10.1101/2025.03.19.644198

bioRxiv · 10.1101/2025.03.19.644198

Pre- and postsynaptic mechanisms of neuronal inhibition assessed through biochemically detailed modelling of GABAB receptor signalling

Mäki-Marttunen, T.·Kismul, J. F.·Pajo, K.·Schulz, J. M.·Manninen, T.·Einevoll, G. T.·Linne, M.-L.·Andreassen, O. A.·Kotaleski, J. H.

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Abstract

GABAB receptors (GABABRs) are an important building block in neural activity. Despite their widely hypothesized role in many basic neuronal functions and mental disorder symptomatology, there is a lack of biophysically and biochemically detailed models of these receptors and the way they mediate neuronal inhibition. Here, we developed a computational model for the activation of GABABRs and its effects on the activation of G protein-coupled inwardly rectifying potassium (GIRK) channels as well as inhibition of voltage-gated Ca2+ channels. To ensure the generality of our modelling framework, we fit our model to electrophysiological data including patch-clamp and intracellular recordings that described both pre- and postsynaptic effects of the receptor activation. We validated our model using data on postsynaptic effects of GABABRs on layer V pyramidal cell firing activity ex vivo and in vivo and confirmed the strong impact of dendritic GIRK channel activation on the neuron output. Finally, we reproduced and dissected the effects of a knockout of RGS7 (a G protein signalling protein) on CA1 pyramidal cell electrophysiological properties, which shows the potential of our model in generating insights on genetic manipulations of the GABABR system and related genetic variants. Our model thus provides a flexible tool for biochemically and biophysically detailed simulations of different aspects of GABABR activation that can reveal both foundational principles of neuronal dynamics and brain disorder-associated traits and treatment options.

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Mäki-Marttunen, T., Kismul, J. F., Pajo, K., Schulz, J. M., Manninen, T., Einevoll, G. T., Linne, M.-L., Andreassen, O. A., Kotaleski, J. H.. 2025-03-19. Pre- and postsynaptic mechanisms of neuronal inhibition assessed through biochemically detailed modelling of GABAB receptor signalling. https://doi.org/10.1101/2025.03.19.644198

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