δ-Containing GABA_A receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the...

In medial prefrontal cortex (mPFC), fast-spiking parvalbumin (PV) interneurons regulate excitability and microcircuit oscillatory activity important for cognition. Although PV interneurons inhibit pyramidal neurons, they themselves express δ subunits of GABA_A receptors important for slow inhibition. However, the specific contribution of δ-containing GABA_A receptors to the function of PV interneurons in mPFC is unclear. We explored cellular, synaptic, and local-circuit activity in PV interneurons and pyramidal neurons in mouse mPFC after selectively deleting δ subunits in PV interneurons (cKO mice). In current-clamp recordings, cKO PV interneurons exhibited a higher frequency of action potentials and higher input resistance than wild-type (WT) PV interneurons. Picrotoxin increased firing and GABA decreased firing in WT PV interneurons but not in cKO PV interneurons. The δ-preferring agonist THIP reduced spontaneous inhibitory postsynaptic currents disproportionately in WT pyramidal neurons compared with cKO pyramidal neurons. In WT slices, depolarizing the network with 400 nM kainate increased firing of pyramidal neurons but had little effect on PV interneuron firing. In contrast, kainate application in cKO slices preferentially activated PV interneurons rather than pyramidal neurons. At the population level, kainate induced broadband increases in local field potentials in WT but not in cKO slices. These results on cells and network activity can be understood through increased excitability of cKO PV interneurons. In summary, our study demonstrates that δ-containing GABA_A receptors in mPFC PV interneurons play a crucial role in regulating their excitability and the phasic inhibition of pyramidal neurons, elucidating intricate mechanisms governing cortical circuitry.NEW & NOTEWORTHY We reveal the critical role of δ-containing GABA_A receptors in parvalbumin interneurons in the medial prefrontal cortex, important for human neuropsychiatric disorders. We demonstrate these receptors' importance in regulating neuronal excitability and network dynamics. δ-containing receptors act as a brake on interneuron activity, maintaining the excitation-inhibition balance in cortical circuits. Our findings provide insights into how disruptions in inhibitory signaling alter network function through a receptor subtype that is a target of neurotherapeutics.