Ion Channels and Morphology Drive Widespread Resonance in Human Cortical Interneurons

Human cortical interneurons exhibit resonance more prevalently than those in mice, with specific ion channels playing a critical role in this phenomenon.

Summary and findings

This study investigated the mechanisms underlying resonance in human cortical interneurons, specifically examining LAMP5, VIP, PV, and SST interneurons. The research utilized Patch-seq, acute electrophysiology, organotypic cultures, and computational modeling. The findings indicate that resonance is significantly more prevalent in human interneurons compared to mouse interneurons.

Abstract

<title>Abstract</title> <p>Cortical neurons respond preferentially to specific network oscillation frequencies—a phenomenon driven by membrane potential resonance. While well studied in human pyramidal neurons, adult human interneuron resonance remains largely unexplored. Using Patch-seq, acute electrophysiology, organotypic cultures, and computational modeling, we investigated the mechanisms underlying resonance across human LAMP5, VIP, PV, and SST interneurons. Resonance is significantly more prevalent in human versus mouse interneurons, peaking in parvalbumin (PV) cells. Unlike human pyramidal neurons, interneuron resonance is independent of cortical depth. Instead, resonance frequency and strength strongly correlate with low input resistance, prominent membrane voltage sag, and enriched expression of HCN1, KCNJ16, and CACNA1A ion channel genes. HCN blockade abolished resonance, while enhanced HCN-mediated sag increased resonance prevalence and strength. Finally, computational models revealed that human morphological features and ion channels sharpen frequency tuning, translating into distinct suprathreshold output under noisy, in vivo-like conditions. These findings reveal fundamental species differences governing human cortical microcircuit dynamics.</p>

Limitations

Not reported in abstract.

Elsewhere in the VIP (Vasoactive Intestinal Polypeptide) corpus