GAD67 Deficiency in Parvalbumin Interneurons Produces Deficits in Inhibitory Transmission and Network Disinhibition in Mouse Prefrontal Cortex
Open accessAbstract
In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.
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GAD67 expression is highly sensitive to input and network activity and directly impacts magnitude of GABAergic transmission.
“As a rate-limiting GABA synthetic enzyme, GAD67 expression is highly sensitive to input and network activity and directly impacts the magnitude GABAergic transmission (43,48).”
From MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex (2015) · cites this paper as [43]
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“Experimental reductions of GAD67 in PV interneurons decrease inhibitory synaptic transmission in pyramidal cells and alter cortical network activity(48-50).”
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- Authors
- Lazarus, M. S., Krishnan, K., & Huang, Z. J.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Lazarus, M. S.
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-11-24
- Volume
- 25
- Issue
- 5
- Pages
- 1290-1296
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC4481616
- OpenAlex
- W2114103149
- Cited by
- 109
- References
- 50
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 6 · 2023: 10 · 2022: 5 · 2021: 13 · 2020: 10 · 2019: 9 · 2018: 10 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 6
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Cold Spring Harbor Laboratory
- National Institute of Mental Health
- National Institute of General Medical Sciences (T32GM008444)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- GAD67, parvalbumin interneurons, GABAergic interneurons, synaptic inhibition, prefrontal cortex, excitation-inhibition balance, homeostatic compensation, neuropsychiatric disorders
- MeSH terms
- Aging, Animals, Electrophysiology, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Interneurons, Male, Mice, Transgenic, Nerve Net, Synaptic Transmission, Parvalbumins, Prefrontal Cortex, Pyramidal Cells, Mice, GABAergic Neurons
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