# Cellular mechanisms of GABAergic inhibition in neocortical dendrites

> **NIH NIH R56** · YALE UNIVERSITY · 2024 · $605,747

## Abstract

SUMMARY
 The development, function, and plasticity of GABAergic circuits in the neocortex are critical processes for
establishing and maintaining normal patterns of brain activity. Moreover, the dysregulation of GABA signaling
is implicated in a number of neuropsychiatric disorders, including schizophrenia and autism. The majority of
studies on GABAergic transmission have focused on fast, phasic signals that inhibit target neurons, negatively
controlling postsynaptic integration and spike generation. However, GABA can also act via tonic currents that
provide a steady-state influence on postsynaptic cells. While tonic GABA largely has been assumed to negatively
regulate neuronal activity, recent data from our lab suggests that it may paradoxically enhance excitability of
dendrites in cortical pyramidal neurons. Whether this unexpected observation extends throughout the
somatodendritic arbor and across cell types is unknown. Additionally, the source of GABA producing tonic
currents remains poorly understood, though evidence suggests it may include the same interneurons mediating
phasic inhibition. In the present study, we propose a combination of electrophysiology, 2-photon imaging,
pharmacology, and optogenetic manipulation both in acute brain slices and in vivo to (1) determine how tonic
GABA currents shape dendritic excitability throughout the arbors of cortical pyramidal neurons, (2) identify the
neuronal sources of GABA mediating tonic currents in the neocortex, and (3) determine the molecular
mechanisms underlying long-term heterosynaptic plasticity of tonic GABAergic signals. Our overall goal is to
understand the links between GABAergic transmission and cortical circuit function. We expect that our results
will generate new avenues for exploring both the cell biology and functional consequences of GABAergic
signaling in the cortex.

## Key facts

- **NIH application ID:** 11111599
- **Project number:** 2R56MH099045-11A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Michael James Higley
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,747
- **Award type:** 2
- **Project period:** 2012-09-20 → 2025-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11111599

## Citation

> US National Institutes of Health, RePORTER application 11111599, Cellular mechanisms of GABAergic inhibition in neocortical dendrites (2R56MH099045-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11111599. Licensed CC0.

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