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Cited by 30Schizophrenia research and treatmentNeuroscience and Neuropharmacology ResearchIon channel regulation and function

Disrupted in Schizophrenia 1 Modulates Medial Prefrontal Cortex Pyramidal Neuron Activity Through cAMP Regulation of Transient Receptor Potential C and Small-Conductance K+ Channels

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El-Hassar, Lynda, Simen, Arthur A., Duque, Alvaro, Patel, Kiran D., Kaczmarek, Leonard K., Arnsten, Amy F.T., Yeckel, Mark F.·2014·Biological Psychiatry
DOI 10.1016/j.biopsych.2013.12.019PMC PMC4104266
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Abstract

Background Disrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulates cyclic adenosine monophosphate (cAMP) signaling by increasing type 4 phosphodiesterase catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons. Methods We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro by dialysis of DISC1 antibodies. Results We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C (TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an α2A-noradrenergic agonist, normalized the function of SK and TRPC channels. Conclusions Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of prefrontal cortex activity through the loss of cAMP regulation of metabotropic glutamate receptor-mediated intracellular Ca2+ waves, SK and TRPC channel activity.

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Cited by

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Authors
El-Hassar, L., Simen, A. A., Duque, A., Patel, K. D., Kaczmarek, L. K., Arnsten, A. F. T., & Yeckel, M. F.
Affiliations
Yale University (US)
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2014-09
Volume
76
Issue
6
Pages
476-485
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2013.12.019
PMC
PMC4104266
OpenAlex
W2039920236
Cited by
30
References
8
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 6 · 2014: 2
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (1RL1AA017536)
  • Kavli Foundation, National Institute of Mental Health (RO1-MH067830, P50-MH068789)
  • National Institutes of Health (DC 01919)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
disrupted-in-schizophrenia 1, DISC1, cAMP signaling, small conductance calcium-activated potassium channels, TRP channels, metabotropic glutamate receptors, intracellular calcium waves, pyramidal neurons, medial prefrontal cortex, guanfacine, schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder
MeSH terms
Cyclic AMP, Animals, Male, Membrane Potentials, Nerve Tissue Proteins, Neurons, Signal Transduction, Rats, Sprague-Dawley, Prefrontal Cortex, Receptors, Metabotropic Glutamate, Mice, Knockout, Calcium Signaling, TRPC Cation Channels, Rats, Small-Conductance Calcium-Activated Potassium Channels

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