Open AccessEffects of a patient-derived de novo coding alteration of CACNA1I in mice connect a schizophrenia risk gene with sleep spindle deficits
Author(s) -
Ayan Ghoshal,
David S. Uygun,
Lingling Yang,
James M. McNally,
Violeta G. López-Huerta,
Mario A. Arias-García,
David Báez-Nieto,
Andrew Allen,
Megan L. Fitzgerald,
Sung-Soon Choi,
Qiangge Zhang,
Jen M. Hope,
Karena Yan,
Xiaohong Mao,
Thomas B. Nicholson,
Kazuo Imaizumi,
Zhanyan Fu,
Guoping Feng,
Ritchie E. Brown,
Robert E. Strecker,
Shaun Purcell,
Jen Q. Pan
Publication year - 2020
Publication title -
translational psychiatry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.652
H-Index - 82
ISSN - 2158-3188
DOI - 10.1038/s41398-020-0685-1
Subject(s) - sleep spindle , haploinsufficiency , biology , missense mutation , non rapid eye movement sleep , neuroscience , mutation , schizophrenia (object oriented programming) , genetics , psychology , eye movement , gene , psychiatry , phenotype
CACNA1I , a schizophrenia risk gene, encodes a subtype of voltage-gated T-type calcium channel Ca V 3.3. We previously reported that a patient-derived missense de novo mutation (R1346H) of CACNA1I impaired Ca V 3.3 channel function. Here, we generated Ca V 3.3-RH knock-in animals, along with mice lacking Ca V 3.3, to investigate the biological impact of R1346H (RH) variation. We found that RH mutation altered cellular excitability in the thalamic reticular nucleus (TRN), where Ca V 3.3 is abundantly expressed. Moreover, RH mutation produced marked deficits in sleep spindle occurrence and morphology throughout non-rapid eye movement (NREM) sleep, while Ca V 3.3 haploinsufficiency gave rise to largely normal spindles. Therefore, mice harboring the RH mutation provide a patient derived genetic model not only to dissect the spindle biology but also to evaluate the effects of pharmacological reagents in normalizing sleep spindle deficits. Importantly, our analyses highlighted the significance of characterizing individual spindles and strengthen the inferences we can make across species over sleep spindles. In conclusion, this study established a translational link between a genetic allele and spindle deficits during NREM observed in schizophrenia patients, representing a key step toward testing the hypothesis that normalizing spindles may be beneficial for schizophrenia patients.