CHLORIDE REGULATION AND POST-SYNAPTIC GABA RECEPTOR SIGNALLING IN CORTICAL PARVALBUMIN-EXPRESSING INTERNEURONS

The dynamic interplay between excitatory and inhibitory neurotransmission is essential for precise cortical activity, accurate information processing, and higher cognitive functions. Parvalbumin-expressing GABAergic interneurons (PV-interneurons) play a central role in regulating excitatory-inhibitory dynamics of cortical circuits and in controlling pyramidal neuron spiking activity. Fast synaptic inhibition onto PV-interneurons is mediated by ligand-gated, chloride-permeable GABA_A receptors, whose effects depend on the transmembrane chloride gradient and the resulting GABA_A receptor reversal potential (EGABA_A). In combination with the membrane potential, EGABA_A determines the driving force for chloride to enter or leave the PV-interneuron when GABAergic synaptic inputs are active. Interestingly, research suggests that unlike other neuronal subtypes, EGABA_A in PV-interneurons is depolarized relative to the membrane potential, favoring chloride efflux upon activation of GABA_A receptors. Consistent with this, we use gramicidin perforated-patch recordings to show that EGABA_A is significantly more depolarized in PV-interneurons compared to neighboring pyramidal neurons within layer 5 of mouse somatosensory cortex. Furthermore, our meta-analysis of single-cell transcriptomic datasets from mouse cortex reveals cell-type-specific differences in genes that regulate chloride homeostasis. To determine the functional significance of this inhibitory signalling in cortical PV-interneurons, we established a head-fixed electrophysiological framework in awake mice and developed molecular tools to selectively manipulate PV-interneuron EGABA_A. These tools include optogenetic manipulations of PV-interneuron EGABA_A and manipulations of chloride regulatory genes that are differentially expressed by PV-interneurons. We present in vivo results examining how chloride-dependent regulation of synaptic inhibition in PV-interneurons influences spontaneous and sensory-evoked cortical activity, and behavioral performance in cognitive tasks.