Pharmacological signature and target-specificity of inhibitory circuits formed by Martinotti cells in the mouse barrel cortex.

In the neocortex, fast synaptic inhibition orchestrates both spontaneous and sensory-evoked activity. GABAergic interneurons (INs) inhibit pyramidal neurons (PNs) directly, modulating their output activity and thus contributing to balance cortical networks. Moreover, several IN subtypes also inhibit other INs, forming specific disinhibitory circuits, which play crucial roles in several cognitive functions. Here, we studied a subpopulation of somatostatin (SST)-positive INs, the Martinotti cells (MCs) in layer 2/3 of the mouse barrel cortex (both sexes). MCs inhibit the distal portion of PN apical dendrites, thus controlling dendrite electrogenesis and synaptic integration. Yet, it is poorly understood whether MCs inhibit other elements of the cortical circuits, and the connectivity properties with non-PN targets are unknown. We found that MCs have a strong preference for PN dendrites, but they also considerably connect with parvalbumin (PV)-positive, vasoactive intestinal peptide (VIP)-expressing and layer 1 (L1) INs. Remarkably, GABAergic synapses from MCs exhibited clear cell-type-specific short-term plasticity (STP). Moreover, whereas the biophysical properties of MC-PN synapses were consistent with distal dendritic inhibition, MC-IN synapses exhibited characteristics of fast perisomatic inhibition. Finally, MC-PN connections used α5-containing GABA A receptors (GABA A Rs), but this subunit was not expressed by the other INs targeted by MCs. We reveal a specialized connectivity blueprint of MCs within different elements of superficial cortical layers. In addition, our results identify α5-GABA A Rs as the molecular fingerprint of MC-PN dendritic inhibition. This is of critical importance, given the role of α5-GABA A Rs in cognitive performance and their involvement in several brain diseases. Significance statement: Martinotti cells (MCs) are a prominent, broad subclass of SST-expressing GABAergic INs, specialized in controlling distal dendrites of PNs and taking part in several cognitive functions. Here we characterize the connectivity pattern of MCs with other INs in the superficial layers (L1 and L2/3) of the mouse barrel cortex. We found that the connectivity pattern of MCs with PNs as well as PV, VIP and L1 INs exhibit target-specific plasticity and biophysical properties. The specificity of α5-GABA A Rs at MC-PN synapses, and the lack or functional expression of this subunit by other cell types, define the molecular identity of MC-PN connections and the exclusive involvement of this inhibitory circuits in α5-dependent cognitive tasks.