Active cortical networks promote shunting fast synaptic inhibition in vivo

Fast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABA_ARs). Despite their fundamental role, it is still not known how GABA_ARs signal in the intact brain. Here, we use in vivo gramicidin recordings to investigate synaptic GABA_AR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anesthetized cortex, synaptic GABA_ARs exert classic hyperpolarizing effects. In contrast, GABA_AR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABA_AR equilibrium potentials (E_GABAAR), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. Synaptic E_GABAAR observed in awake cortex facilitates the desynchronizing effects of inhibitory inputs upon local networks, which increases the flexibility of spiking responses to external inputs. Our findings therefore suggest that GABA_AR signaling adapts to optimize cortical functions.