# Rapid inhibitory circuit plasticity as a homeostatic mechanism in cerebral cortex

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $344,055

## Abstract

Experience robustly regulates the development and function of GABAergic inhibitory circuits in cerebral
cortex, but the purpose of this inhibitory circuit plasticity is unclear. Recent findings in rodent somatosensory
(S1) and visual cortex suggest that inhibitory plasticity may contribute to homeostatic stabilization of firing
rate in cortical networks. We recently discovered that during competitive map plasticity in S1, sensory
deprivation weakens parvalbumin (PV) inhibitory circuits very rapidly (< 1 day). This is faster than classical
homeostatic mechanisms like synaptic scaling, and promotes firing rate stability in the S1 network. We
propose that PV circuit plasticity functions as a rapid, bidirectional homeostat, operating on the time scale of
hours, and that its role is to stabilize cortical firing rate. We propose that it accomplishes this by adaptively
altering PV circuit gain and excitation-inhibition (E-I) ratio in local pyramidal cells as a function of the recent
history of network activity. This rapid inhibitory plasticity may be a major contributor to controlling firing rate in
cerebral cortex.
Here, we test this hypothesis, using L2/3 of mouse whisker S1 cortex as a model system. In Aim 1,
we use slice physiology and layer-specific optogenetics to measure how whisker deprivation alters the gain of
L4-L2/3 feedforward and L2/3-L2/3 recurrent inhibitory circuits, and quantify the dynamics of this plasticity.
We test whether direct chemogenetic modulation of pyramidal cell firing rate induces inhibitory circuit
plasticity, whether this is bidirectional, and whether it is general across cortical areas. In Aim 2, we use dual
whole-cell recording to identify the specific synaptic and cellular changes that mediate rapid inhibitory
plasticity in PV and Somatostatin (SOM) circuits. In Aim 3, we use 2-photon calcium imaging and chronic
extracellular unit recording to characterize firing rate homeostasis in L2/3, determine its magnitude and
dynamics across age, and measure its relationship to inhibitory circuit plasticity.
Breakdown of inhibitory homeostasis could contribute to circuit dysfunction in autism, schizophrenia,
and other disorders. In Aim 4, we test this hypothesis by asking whether inhibition or inhibitory homeostasis
is disrupted in cortex in several transgenic mouse models of autism. Preliminary data show that excitation-inhibition ratio is disrupted in common across four genetically unrelated mouse models. This provides key
support for the long-held E-I ratio model of autism. Overall, this project will reveal whether inhibitory circuit
plasticity is an important mechanism for rapid homeostasis of cortical firing rate, and whether its disruption
may contribute to neurological disease.

## Key facts

- **NIH application ID:** 9828790
- **Project number:** 5R01NS105333-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Daniel Feldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,055
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828790

## Citation

> US National Institutes of Health, RePORTER application 9828790, Rapid inhibitory circuit plasticity as a homeostatic mechanism in cerebral cortex (5R01NS105333-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9828790. Licensed CC0.

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