Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania
Open accessAbstract
Background Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood.Methods Using ex vivo whole-cell patch-clamp electrophysiology in ClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression of Gria1 in the NAc and behavioral assays were also used.Results Compared with wild-type mice, ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functional Gria1 in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state.Conclusions Together, our findings demonstrate that NAc excitatory signaling via Gria1 expression is integral to the effects of Clock gene disruption on manic-like behaviors.
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Circadian genes in brain regions outside the SCN contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and disruption of these functions might contribute to brain disorders.
“circadian genes in other brain regions outside of this central pace-maker also contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and the disruption of these functions might contribute to brain disorders264,304–315”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [312]
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Rhythms of life: circadian disruption and brain disorders across the lifespan
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- Authors
- Parekh, P. K., Becker-Krail, D., Sundaravelu, P., Ishigaki, S., Okado, H., Sobue, G., Huang, Y., & McClung, C. A.
- Affiliations
- University of Pittsburgh Medical Center (US)
- Nagoya University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- McClung, Colleen A.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 84
- Issue
- 11
- Pages
- 817-826
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5745309
- OpenAlex
- W2727422731
- Cited by
- 48
- References
- 53
- Citations by year
- 2026: 8 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 10 · 2021: 1 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 1
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (15K09310, 26117001, 26117004)
- National Institute of Mental Health (R01MH082876, R01MH101147)
- National Institute on Drug Abuse (R01DA023988, R01DA035805, R01DA039865)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- clock genes, bipolar mania, GluR1, nucleus accumbens, synaptic plasticity, AMPA receptors, excitatory synaptic transmission, medium spiny neurons, intrinsic excitability, circadian rhythm, circadian rhythm disruption, reward sensitivity, manic-like behavior
- MeSH terms
- Animals, Bipolar Disorder, Circadian Rhythm, Female, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Synaptic Transmission, Neuronal Plasticity, Neurons, Nucleus Accumbens, Receptors, AMPA, Mice, Knockout, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Mice, CLOCK Proteins
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