Dopamine D4Receptors Regulate AMPA Receptor Trafficking and Glutamatergic Transmission in GABAergic Interneurons of Prefrontal Cortex
Open accessAbstract
GABAergic interneurons in prefrontal cortex (PFC) play a critical role in cortical circuits by providing feedforward and feedback inhibition and synchronizing neuronal activity. Impairments in GABAergic inhibition to PFC pyramidal neurons have been implicated in the abnormal neural synchrony and working memory disturbances in schizophrenia. The dopamine D 4 receptor, which is strongly linked to neuropsychiatric disorders, such as attention deficit–hyperactivity disorder (ADHD) and schizophrenia, is highly expressed in PFC GABAergic interneurons, while the physiological role of D 4 in these interneurons is largely unknown. In this study, we found that D 4 activation caused a persistent suppression of AMPAR-mediated synaptic transmission in PFC interneurons. This effect of D 4 receptors on AMPAR-EPSC was via a mechanism dependent on actin/myosin V motor-based transport of AMPA receptors, which was regulated by cofilin, a major actin depolymerizing factor. Moreover, we demonstrated that the major cofilin-specific phosphatase Slingshot, which was activated by calcineurin downstream of D 4 signaling, was required for the D 4 regulation of glutamatergic transmission. Thus, D 4 receptors, by using the unique calcineurin/Slingshot/cofilin signaling mechanism, regulate actin dynamics and AMPAR trafficking in PFC GABAergic interneurons. It provides a potential mechanism for D 4 receptors to control the excitatory synaptic strength in local-circuit neurons and GABAergic inhibition in the PFC network, which may underlie the role of D 4 receptors in normal cognitive processes and mental disorders.
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D4 receptors suppress AMPARs in PFC GABAergic interneurons via calcineurin/Slingshot/cofilin signaling.
“D4 receptors suppress AMPARs in PFC GABAergic interneurons via the unique calcineurin/Slingshot/cofilin signaling mechanism 64.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [64]
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- Authors
- Yuen, E. Y., & Yan, Z.
- Affiliations
- University at Buffalo, State University of New York (US)
- Corresponding author
- Yan, Zhen
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-01-14
- Volume
- 29
- Issue
- 2
- Pages
- 550-562
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2768380
- OpenAlex
- W2159807079
- Cited by
- 81
- References
- 81
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 8 · 2016: 4 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 11
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH-084233, R01MH084233)
- National Institute of Neurological Disorders and Stroke (NS-048911, R01NS048911)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- dopamine D4 receptor, AMPA receptor trafficking, GABAergic interneurons, prefrontal cortex, glutamatergic neurotransmission, cofilin, calcineurin, actin dynamics, synaptic inhibition, schizophrenia, attention deficit hyperactivity disorder
- MeSH terms
- Analysis of Variance, Animals, Colchicine, Enzyme Inhibitors, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Interneurons, Mice, Transgenic, Microfilament Proteins, Synaptic Transmission, Phalloidine, Phosphoric Monoester Hydrolases, Transfection, Dopamine Agents, Prefrontal Cortex, Receptors, AMPA, Patch-Clamp Techniques, Glutamic Acid, Calcineurin, Protein Transport, RNA, Small Interfering, Green Fluorescent Proteins, Tubulin Modulators, Receptors, Dopamine D4, Mice, Rats, In Vitro Techniques
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