Phylogenetic divergence of GABA receptor signaling in neocortical networks over adult life.

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