Transcriptomically-Guided Pharmacological Experiments in Neocortical and Hippocampal NPY-Positive GABAergic...

Cortical GABAergic interneurons have been shown to fulfil important roles by inhibiting excitatory principal neurons. Recent transcriptomic studies have confirmed seminal discoveries that used anatomic and electrophysiological methods highlighting the existence of multiple different classes of GABAergic interneurons. Although some of these studies have emphasized that inter-regional differences may exist for a given class, the extent of such differences remains unknown. To address this problem, we used single-cell Patch-RNAseq to characterize neuropeptide Y (NPY)-positive GABAergic interneurons in superficial layers of the primary auditory cortex (AC) and in distal layers of area CA3 in mice. We found that more than 300 genes are differentially expressed in NPY-positive neurons between these two brain regions. For example, the AMPA receptor (AMPAR) auxiliary subunit Shisa9/CKAMP44 and the 5HT2a receptor (5HT2aR) are significantly higher expressed in auditory NPY-positive neurons. These findings guided us to perform pharmacological experiments that revealed a role for 5HT2aRs in auditory NPY-positive neurons. Specifically, although the application of 5HT led to a depolarization of both auditory and CA3 NPY-positive neurons, the 5HT2aR antagonist ketanserin only reversed membrane potential changes in auditory NPY-positive neurons. Our study demonstrates the potential of single-cell transcriptomic studies in guiding directed pharmacological experiments.