Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress

Bavley, Charlotte C.; Kabir, Zeeba D.; Walsh, Alexander P.; Kosovsky, Maria; Hackett, Jonathan E.; Sun, Herie; Vázquez‐Rosa, Edwin; Cintrón-Pérez, Coral J.; Miller, Emiko; Koh, Yeojung; Pieper, Andrew A.; Rajadhyaksha, Anjali M.

doi:10.1038/s41380-020-0730-8

Cited by 17 publications

(16 citation statements)

References 56 publications

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“…Mice were then administered either vehicle (TBI-Veh, Sham-Veh) or P7C3-A20 (10 mg⋅kg −1 ⋅day −1 intraperitoneally [IP]; TBI-P7C3-A20) for 4 wk. P7C3-A20 is an aminopropyl carbazole that elevates cellular nicotinamide adenine dinucleotide, enhances survival of adult-born young hippocampal neurons, and has been shown to preserve mature neurons and improve cognition in various models of nervous system disease and injury ( 25 – 45 ). Immediately after treatment completion, cognitive function in the 15-mo-old animals was evaluated through Morris water maze (MWM) testing.…”

Section: Resultsmentioning

confidence: 99%

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

Vázquez‐Rosa

Shin

Dhar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Chronic neurodegeneration in survivors of traumatic brain injury (TBI) is a major cause of morbidity, with no effective therapies to mitigate this progressive and debilitating form of nerve cell death. Here, we report that pharmacologic restoration of the blood–brain barrier (BBB), 12 mo after murine TBI, is associated with arrested axonal neurodegeneration and cognitive recovery, benefits that persisted for months after treatment cessation. Recovery was achieved by 30 d of once-daily administration of P7C3-A20, a compound that stabilizes cellular energy levels. Four months after P7C3-A20, electron microscopy revealed full repair of TBI-induced breaks in cortical and hippocampal BBB endothelium. Immunohistochemical staining identified additional benefits of P7C3-A20, including restoration of normal BBB endothelium length, increased brain capillary pericyte density, increased expression of BBB tight junction proteins, reduced brain infiltration of immunoglobulin, and attenuated neuroinflammation. These changes were accompanied by cessation of TBI-induced chronic axonal degeneration. Specificity for P7C3-A20 action on the endothelium was confirmed by protection of cultured human brain microvascular endothelial cells from hydrogen peroxide-induced cell death, as well as preservation of BBB integrity in mice after exposure to toxic levels of lipopolysaccharide. P7C3-A20 also protected mice from BBB degradation after acute TBI. Collectively, our results provide insights into the pathophysiologic mechanisms behind chronic neurodegeneration after TBI, along with a putative treatment strategy. Because TBI increases the risks of other forms of neurodegeneration involving BBB deterioration (e.g., Alzheimer’s disease, Parkinson’s disease, vascular dementia, chronic traumatic encephalopathy), P7C3-A20 may have widespread clinical utility in the setting of neurodegenerative conditions.

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Section: Resultsmentioning

confidence: 99%

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

Vázquez‐Rosa

Shin

Dhar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, Ca V 1 channels have well-de ned presynaptic and postsynaptic functions in neurons [1][2][3][4], but recent work has revealed a crucial role for Ca V 1.2 in regulating myelination and proliferation of oligodendrocytes [53][54][55]. Anxiety-like phenotypes [11,12] and abnormal fear learning [14,56] are observed in mice where Ca V 1.2 is deleted in glia as well as neurons, but not in other neuron-speci c conditional knockouts [28, 29,57] including the work reported here. This suggests that anxiety and fear phenotypes related to Ca V 1.2 may be driven by a non-neuronal cell type.…”

Section: Discussionmentioning

confidence: 99%

“…Breeding pairs always consisted of a Cre positive female (Cre/+) and a Cre negative male (+/+) to avoid germline recombination in offspring as described previously in the Syn1-Cre mouse line [33]. All mice were adults (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)…”

Section: Micementioning

confidence: 99%

“…The alpha subunit of Ca V 1.2 is encoded by the gene CACNA1C, which has been robustly linked to increased risk for many neuropsychiatric disorders including autism, schizophrenia, major depression, and bipolar disorder [5][6][7][8][9][10][11]. Ca V 1.2 haploinsu cient mice, which lack one copy of Ca V 1.2 in all tissues, exhibit antidepressant-like phenotypes, hypoactivity, anxiety-like behaviors, increased fear responses, and changes in social behavior [11][12][13][14][15][16][17]. However, these mice have reduced Ca V 1.2 expression in all tissues throughout the body; therefore, it is unclear which cognitive, motor, and affective behaviors are directly related to Ca V 1.2 expression in neurons.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice

Klomp

Plumb

Mehr

et al. 2022

Preprint

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The gene CACNA1C, which encodes the L-type calcium channel CaV1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of CaV1.2 results in cognitive, affective, and motor deficits. However, it is unclear if the phenotypes described in these studies result from loss of CaV1.2 from neurons or other central nervous system cell types. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of CaV1.2 (neuronal CaV1.2 cKO). We found that neuronal CaV1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal CaV1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal CaV1.2 cKO mice did not display normal social preference, whereas female neuronal CaV1.2 cKO mice did. In agreement with previous work, neuronal CaV1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal CaV1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of CaV1.2.

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“…LTCCs enable activity-dependent calcium (Ca 2+ ) transport into neurons for excitation-transcription coupling and long-term potentiation (18,19). Ca v 1.2α1 has been linked to anxiety-like and depressivelike behavior, stress responses, addiction, recovery from posttraumatic stress, and survival of adult-born young hippocampal neurons (20)(21)(22). Ca v 1.2α1 also participates in channeltransporter functional networks between the plasma membrane and mitochondria, where its ablation curbs mitochondrial respiration and reactive oxygen species generation during excitotoxic injury (23,24).…”

Section: Significancementioning

confidence: 99%

Dual-process brain mitochondria isolation preserves function and clarifies protein composition

Noterman

Chaubey

Lin‐Rahardja

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The brain requires continuously high energy production to maintain ion gradients and normal function. Mitochondria critically undergird brain energetics, and mitochondrial abnormalities feature prominently in neuropsychiatric disease. However, many unique aspects of brain mitochondria composition and function are poorly understood. Developing improved neuroprotective therapeutics thus requires more comprehensively understanding brain mitochondria, including accurately delineating protein composition and channel–transporter functional networks. However, obtaining pure mitochondria from the brain is especially challenging due to its distinctive lipid and cell structure properties. As a result, conflicting reports on protein localization to brain mitochondria abound. Here we illustrate this problem with the neuropsychiatric disease-associated L-type calcium channel Cav1.2α1 subunit previously observed in crude mitochondria. We applied a dual-process approach to obtain functionally intact versus compositionally pure brain mitochondria. One branch utilizes discontinuous density gradient centrifugation to isolate semipure mitochondria suitable for functional assays but unsuitable for protein localization because of endoplasmic reticulum (ER) contamination. The other branch utilizes self-forming density gradient ultracentrifugation to remove ER and yield ultrapure mitochondria that are suitable for investigating protein localization but functionally compromised. Through this process, we evaluated brain mitochondria protein content and observed the absence of Cav1.2α1 and other previously reported mitochondrial proteins, including the NMDA receptor, ryanodine receptor 1, monocarboxylate transporter 1, excitatory amino acid transporter 1, and glyceraldehyde 3-phosphate dehydrogenase. Conversely, we confirmed mitochondrial localization of several plasma membrane proteins previously reported to also localize to mitochondria. We expect this dual-process isolation procedure will enhance understanding of brain mitochondria in both health and disease.

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Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress

Cited by 17 publications

References 56 publications

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition

Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice

Dual-process brain mitochondria isolation preserves function and clarifies protein composition

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