Inhibition of BK channels by GABAb receptors enhances intrinsic excitability of layer 2/3 vasoactive intestinal polypeptide‐expressing interneurons in mouse neocortex

GABAb receptors (GABAbRs) affect many signalling pathways, and hence the net effect of the activity of these receptors depends upon the specific ion channels that they are linked to, leading to different effects on specific neuronal populations. Typically, GABAbRs suppress neuronal activity in the cerebral cortex. Previously, we found that neocortical parvalbumin-expressing cells are strongly inhibited through GABAbRs, whereas somatostatin interneurons are immune to this modulation. Here, we employed in vitro whole-cell patch-clamp recordings to study whether GABAbRs modulate the activity of vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in layer (L) 2/3 of the mouse primary somatosensory cortex. Utilizing machine learning algorithms (hierarchical clustering and principal component analysis), we revealed that one VIP-IN cluster (about 68% of all VIP-INs) was sensitive to GABAbR activation. Paradoxically, when recordings were performed in standard conditions with high extracellular Ca²⁺ level, GABAbRs indirectly inhibited the activity of large conductance voltage- and calcium-activated potassium (BK) channels and reduced GABAaR-mediated inhibition, leading to an increase in intrinsic excitability of these interneurons. However, a classical inhibitory effect of GABAbRs on L2/3 VIP-INs was observed in modified artificial cerebrospinal fluid with physiological (low) Ca²⁺ concentration. Our results are essential for a deeper understanding of mechanisms underlying the modulation of cortical networks. KEY POINTS: Layer 2/3 vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory cortex cluster into three electrophysiological types differentially sensitive to GABAb receptors (GABAbRs). The majority of VIP-INs (type 1, about 68% of all VIP-INs) are regulated through pre- and postsynaptic GABAbRs, while a subset of these interneurons (types 2 and 3) is controlled only presynaptically. The net effect of GABAbR activation on VIP-IN excitability depends on [Ca²⁺] in artificial cerebrospinal fluid. When [Ca²⁺] is high (2.5 mM), GABAbRs indirectly inhibit BK channels and reduce GABAaR inhibition leading to increased intrinsic excitability of type 1 VIP-INs. When [Ca²⁺] is low (1 mM), which is more physiological, BK channels do not regulate the intrinsic excitability of VIP-INs and thus postsynaptic GABAbRs canonically decrease the intrinsic excitability of type 1 VIP-INs.