Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress
العنوان: | Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress |
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المؤلفون: | Andrew A. Pieper, Emiko Miller, Edwin Vázquez-Rosa, Alexander P. Walsh, Coral J. Cintrón-Pérez, Jonathan E. Hackett, Herie Sun, Anjali M. Rajadhyaksha, Yeojung Koh, Charlotte C. Bavley, Maria Kosovsky, Zeeba D. Kabir |
المصدر: | Mol Psychiatry |
بيانات النشر: | Springer Science and Business Media LLC, 2020. |
سنة النشر: | 2020 |
مصطلحات موضوعية: | Male, 0301 basic medicine, Calcium Channels, L-Type, Dopamine, Conditioning, Classical, Hippocampal formation, Neuroprotection, Article, Extinction, Psychological, Stress Disorders, Post-Traumatic, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, Therapeutic approach, 0302 clinical medicine, Animals, Humans, Medicine, Molecular Biology, Neurons, business.industry, Traumatic stress, Fear, Extinction (psychology), Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, Anxiety, Neuron, medicine.symptom, business, Neuroscience, 030217 neurology & neurosurgery, medicine.drug |
الوصف: | Post-traumatic stress disorder (PTSD) is characterized by persistent fear memory of remote traumatic events, mental re-experiencing of the trauma, long-term cognitive deficits, and PTSD-associated hippocampal dysfunction. Extinction-based therapeutic approaches acutely reduce fear. However, many patients eventually relapse to the original conditioned fear response. Thus, understanding the underlying molecular mechanisms of this condition is critical to developing new treatments for patients. Mutations in the neuropsychiatric risk gene CACNA1C, which encodes the Ca(v)1.2 isoform of the L-type calcium channel, have been implicated in both PTSD and highly comorbid neuropsychiatric conditions, such as anxiety and depression. Here, we report that male mice with global heterozygous loss of cacna1c exhibit exacerbated contextual fear that persists at remote time points (up to 180 days after shock), despite successful acute extinction training, reminiscent of PTSD patients. Because dopamine has been implicated in contextual fear memory, and Ca(v)1.2 is a downstream target of dopamine D1-receptor (D1R) signaling, we next generated mice with specific deletion of cacna1c from D1R-expressing neurons (D1-cacna1c(KO) mice). Notably, D1-cacna1c(KO) mice also show the same exaggerated remote contextual fear, as well as persistently elevated anxiety-like behavior and impaired spatial memory at remote time points, reminiscent of chronic anxiety in treatment-resistant PTSD. We also show that D1-cacna1c(KO) mice exhibit elevated death of young hippocampal neurons, and that treatment with the neuroprotective agent P7C3-A20 eradicates persistent remote fear. Augmenting survival of young hippocampal neurons may thus provide an effective therapeutic approach for promoting durable remission of PTSD, particularly in patients with CACNA1C mutations or other genetic aberrations that impair calcium signaling or disrupt the survival of young hippocampal neurons. |
تدمد: | 1476-5578 1359-4184 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3af405643344edc7fd8f37dfdb93fc51 https://doi.org/10.1038/s41380-020-0730-8 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....3af405643344edc7fd8f37dfdb93fc51 |
قاعدة البيانات: | OpenAIRE |
تدمد: | 14765578 13594184 |
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