iGABASnFr Imaging Reveals that GABA Clearance Is Rapidly Overwhelmed in the Cerebral Cortex
- 1Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
- 2Neuroscience Program, Tufts Graduate School of Biomedical Sciences, Boston, Massachusetts 02111
- 3Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892
Abstract
Both phasic and tonic GABAergic activities in the cortex are shaped by the clearance of GABA from the extracellular space by GABA transporters (GATs). However, estimates of the time-course of GAT activity from GAT currents, GABAA, and GABAB electrophysiological recordings range from tens of milliseconds to multiple seconds. These estimates may reflect receptor properties rather than extracellular GABA dynamics. Understanding how long GABA is free in the extracellular space is key to understanding how inhibition controls activity but has been technically challenging. Here, we utilize the fluorescent GABA sensor, iGABASnFr, to enable us to optically assay extracellular GABA dynamics following bursts of synaptic activity. In the mouse cerebral cortex of either sex, we show that GABA rapidly disperses from release sites via diffusion, with very little role for active transport by GATs. Following diffusion from the sites of release, GABA then accumulates in the extracellular space, where GATs require hundreds of milliseconds to remove it. For areas of high-density GABA release or during bursts of activity, this clearance is further slowed. Continued GABA release and summation in the extracellular space for bursts of activity contrasts with recorded inhibitory postsynaptic current (IPSC) signals, which rapidly depress with additional stimuli, suggesting a disconnect between IPSCs and extracellular GABA. Lastly, the resulting extracellular accumulation of GABA can act heterosynaptically by activating and/or desensitizing GABAA receptors. Together, this raises new questions about how GABAergic inhibition works to shape network function and suggests a spatiotemporal continuum of extracellular GABA.
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BibTeX
@article{gariepy2026igabasnfr,
title = {{iGABASnFr Imaging Reveals that GABA Clearance Is Rapidly Overwhelmed in the Cerebral Cortex}},
author = {Reyna L. Gariepy and Jesse B. Blackman and Anushree S. Gupte and Jeffrey S. Diamond and Chris G. Dulla and Moritz Armbruster},
journal = {The Journal of Neuroscience},
year = {2026},
month = oct,
doi = {10.1523/jneurosci.0354-26.2026},
url = {https://doi.org/10.1523/jneurosci.0354-26.2026},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - iGABASnFr Imaging Reveals that GABA Clearance Is Rapidly Overwhelmed in the Cerebral Cortex
AU - Reyna L. Gariepy
AU - Jesse B. Blackman
AU - Anushree S. Gupte
AU - Jeffrey S. Diamond
AU - Chris G. Dulla
AU - Moritz Armbruster
PY - 2026
DA - 2026/10/14
JO - The Journal of Neuroscience
DO - 10.1523/jneurosci.0354-26.2026
UR - https://doi.org/10.1523/jneurosci.0354-26.2026
AB - Both phasic and tonic GABAergic activities in the cortex are shaped by the clearance of GABA from the extracellular space by GABA transporters (GATs). However, estimates of the time-course of GAT activity from GAT currents, GABAA, and GABAB electrophysiological recordings range from tens of milliseconds to multiple seconds. These estimates may reflect receptor properties rather than extracellular GABA dynamics. Understanding how long GABA is free in the extracellular space is key to understanding how inhibition controls activity but has been technically challenging. Here, we utilize the fluorescent GABA sensor, iGABASnFr, to enable us to optically assay extracellular GABA dynamics following bursts of synaptic activity. In the mouse cerebral cortex of either sex, we show that GABA rapidly disperses from release sites via diffusion, with very little role for active transport by GATs. Following diffusion from the sites of release, GABA then accumulates in the extracellular space, where GATs require hundreds of milliseconds to remove it. For areas of high-density GABA release or during bursts of activity, this clearance is further slowed. Continued GABA release and summation in the extracellular space for bursts of activity contrasts with recorded inhibitory postsynaptic current (IPSC) signals, which rapidly depress with additional stimuli, suggesting a disconnect between IPSCs and extracellular GABA. Lastly, the resulting extracellular accumulation of GABA can act heterosynaptically by activating and/or desensitizing GABAA receptors. Together, this raises new questions about how GABAergic inhibition works to shape network function and suggests a spatiotemporal continuum of extracellular GABA.
SN - 0270-6474
SN - 1529-2401
ER -