Extrasynaptic-GABA-mediated neuromodulation in a sensory cortical neural network

Simulating a neural network model of an early sensory cortical area, we investigated how gamma-aminobutyric acid (GABA) accumulated in extracellular space (ambient GABA), which depends on the synaptic activity of GABAergic interneurons, acts on the GABAa-receptors located on extrasynaptic membrane regions of principal cells (P), feedback inhibitory cells (F) and lateral inhibitory cells (L). The ambient GABA enhanced the selective responsiveness of P-cells to a target feature stimulus, if it acted on the extrasynaptic GABAa-receptors of P-cells. The ambient GABA led to depolarizing P-cells during ongoing (spontaneous) neuronal-activity periods, if it acted on the extrasynaptic GABAa-receptors of F or L cells. This membrane depolarization contributed to establishing an ongoing subthreshold neuronal state, by which the P-cells could respond quickly to the target stimulus. We suggest that the combinatorial inhibition of P, F, and L cells, meditated by extrasynaptic GABAa-receptors recognizing ambient GABA, is crucial for processing the information of relevant sensory features and for establishing an ongoing subthreshold cortical state that prepares as a ready state for subsequent sensory input. A failure in neuronal-activity-dependent regulation of ambient GABA, stemming largely from the depletion of GABA in extracellular space during senescence, may cause the degeneration of intracortical inhibition that leads to cognitive dysfunction in old animals.