Ion Channels and Morphology Drive Widespread Resonance in Human Cortical Interneurons

Abstract

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.

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BibTeX RIS

BibTeX

@misc{mansvelder2026channels,
  title = {{Ion Channels and Morphology Drive Widespread Resonance in Human Cortical Interneurons}},
  author = {Huibert Mansvelder and Natia Shamugia and Robin Weiler and Tim Heistek and Kamiliam Nasirova and Sarah Scott and Sara Vargas and Brian Lee and Rachel Dalley and Brian Kalmbach and Jonathan Ting and Ed Lein and Natalia Goriounova},
  howpublished = {Research Square},
  year = {2026},
  month = oct,
  doi = {10.21203/rs.3.rs-11136357/v1},
  url = {https://doi.org/10.21203/rs.3.rs-11136357/v1},
  note = {CC BY 4.0},
}

RIS

TY  - UNPB
TI  - Ion Channels and Morphology Drive Widespread Resonance in Human Cortical Interneurons
AU  - Huibert Mansvelder
AU  - Natia Shamugia
AU  - Robin Weiler
AU  - Tim Heistek
AU  - Kamiliam Nasirova
AU  - Sarah Scott
AU  - Sara Vargas
AU  - Brian Lee
AU  - Rachel Dalley
AU  - Brian Kalmbach
AU  - Jonathan Ting
AU  - Ed Lein
AU  - Natalia Goriounova
PY  - 2026
DA  - 2026/10/12
PB  - Research Square
DO  - 10.21203/rs.3.rs-11136357/v1
UR  - https://doi.org/10.21203/rs.3.rs-11136357/v1
AB  - 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.
SN  - 2693-5015
ER  -

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