Abstract

GABA_B receptors (GABA_BRs) 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 GABA_BRs 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 modeling 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 GABA_BRs 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 signaling protein) on CA1 pyramidal cell electrophysiological properties, which shows the potential of our model in generating insights on genetic manipulations of the GABA_BR system and related genetic variants. Our model thus provides a flexible tool for biochemically and biophysically detailed simulations of different aspects of GABA_BR activation that can reveal both foundational principles of neuronal dynamics and brain disorder-associated traits and treatment options.