Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/-) mice
Open accessAbstract
Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven γ oscillations in cognitive domains at the core of schizophrenia.
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In mice, the intrinsic electrophysiological properties of PV expressing interneurons in the frontal cortex change significantly during prepubertal development and into mid adolescence (P45-49).
“In mice, the intrinsic electrophysiological properties of PV expressing interneurons in the frontal cortex change significantly during prepubertal development (Yang et al., 2012) and into mid adolescence (P45–49; (Cho et al., 2015)).”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Cho et al., 2015
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- Authors
- Cho, K. K. A., Hoch, R., Lee, A. T., Patel, T., Rubenstein, J. L. R., & Sohal, V. S.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Sohal, Vikaas S.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 85
- Issue
- 6
- Pages
- 1332-1343
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4503262
- OpenAlex
- W2038977021
- Cited by
- 329
- References
- 39
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 38 · 2023: 19 · 2022: 25 · 2021: 41 · 2020: 33 · 2019: 29 · 2018: 35 · 2017: 25 · 2016: 37 · 2015: 7
- FWCI
- 28.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- International Mental Health Research Organization
- National Alliance for Research on Schizophrenia and Depression
- University of California, San Francisco
- National Institute of Mental Health (T32MH089920, T32MH89920, R00MH085946, R01MH100292, DP2MH100011, R37MH049428)
- NIH Office of the Director
- National Center for Chronic Disease Prevention and Health Promotion (DP2 MH100011)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- gamma oscillations, fast-spiking interneurons, GABAergic interneurons, prefrontal cortex, cognitive flexibility, schizophrenia, adolescence, interneuron inhibition, schizophrenia endophenotype
- MeSH terms
- Animals, Behavior, Animal, Cognition, Disease Models, Animal, Interneurons, Male, Parvalbumins, Schizophrenia, Prefrontal Cortex, Homeodomain Proteins, Mice, Gamma Rhythm
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