دورية أكاديمية
أعرض في EDS

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α.

التفاصيل البيبلوغرافية
العنوان: Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α.
المؤلفون: Kabir ZD; Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA., Che A; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA., Fischer DK; Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA., Rice RC; Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA., Rizzo BK; Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA., Byrne M; Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA., Glass MJ; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA., De Marco Garcia NV; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA., Rajadhyaksha AM; Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.; Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA.; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
المصدر: Molecular psychiatry [Mol Psychiatry] 2017 Aug; Vol. 22 (8), pp. 1096-1109. Date of Electronic Publication: 2017 Jun 06.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Specialist Journals Country of Publication: England NLM ID: 9607835 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5578 (Electronic) Linking ISSN: 13594184 NLM ISO Abbreviation: Mol Psychiatry Subsets: MEDLINE
أسماء مطبوعة: Publication: 2000- : Houndmills, Basingstoke, UK : Nature Publishing Group Specialist Journals
Original Publication: Houndmills, Hampshire, UK ; New York, NY : Stockton Press, c1996-
مواضيع طبية MeSH: Calcium Channels, L-Type/*drug effects , Calcium Channels, L-Type/*metabolism, Animals ; Anxiety ; Behavior, Animal/drug effects ; Calcium/metabolism ; Calcium Channels, L-Type/genetics ; Disease Models, Animal ; Eukaryotic Initiation Factor-2/genetics ; Eukaryotic Initiation Factor-2/metabolism ; Eukaryotic Initiation Factors/genetics ; Eukaryotic Initiation Factors/metabolism ; Genetic Predisposition to Disease/genetics ; Hippocampus/metabolism ; Humans ; Mice ; Mice, Knockout ; Neurons/metabolism ; Prosencephalon/metabolism ; Pyramidal Cells/metabolism ; Social Behavior
مستخلص: CACNA1C, encoding the Ca v 1.2 subunit of L-type Ca 2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Ca v 1.2 channels play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Ca v 1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Ca v 1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.
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معلومات مُعتمدة: R00 MH095825 United States MH NIMH NIH HHS; R01 DA029122 United States DA NIDA NIH HHS; R01 MH110553 United States MH NIMH NIH HHS
المشرفين على المادة: 0 (CACNA1C protein, mouse)
0 (Calcium Channels, L-Type)
0 (Eukaryotic Initiation Factor-2)
0 (Eukaryotic Initiation Factors)
0 (eIF-4B)
SY7Q814VUP (Calcium)
تواريخ الأحداث: Date Created: 20170607 Date Completed: 20171113 Latest Revision: 20181113
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC5863913
DOI: 10.1038/mp.2017.124
PMID: 28584287
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5578
DOI:10.1038/mp.2017.124