You are here

Transl Psychiatry DOI:10.1038/s41398-020-0685-1

Effects of a patient-derived de novo coding alteration of CACNA1I in mice connect a schizophrenia risk gene with sleep spindle deficits.

Publication TypeJournal Article
Year of Publication2020
AuthorsGhoshal, A, Uygun, DS, Yang, L, McNally, JM, Lopez-Huerta, VG, Arias-Garcia, MA, Baez-Nieto, D, Allen, A, Fitzgerald, M, Choi, S, Zhang, Q, Hope, JM, Yan, K, Mao, X, Nicholson, TB, Imaizumi, K, Fu, Z, Feng, G, Brown, RE, Strecker, RE, Purcell, SM, Pan, JQ
JournalTransl Psychiatry
Volume10
Issue1
Pages29
Date Published2020 01 23
ISSN2158-3188
Abstract

CACNA1I, a schizophrenia risk gene, encodes a subtype of voltage-gated T-type calcium channel Ca3.3. We previously reported that a patient-derived missense de novo mutation (R1346H) of CACNA1I impaired Ca3.3 channel function. Here, we generated Ca3.3-RH knock-in animals, along with mice lacking Ca3.3, to investigate the biological impact of R1346H (RH) variation. We found that RH mutation altered cellular excitability in the thalamic reticular nucleus (TRN), where Ca3.3 is abundantly expressed. Moreover, RH mutation produced marked deficits in sleep spindle occurrence and morphology throughout non-rapid eye movement (NREM) sleep, while Ca3.3 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.

DOI10.1038/s41398-020-0685-1
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32066662?dopt=Abstract

Alternate JournalTransl Psychiatry
PubMed ID32066662
PubMed Central IDPMC7026444
Grant ListU54 NS108874 / NS / NINDS NIH HHS / United States
MH097104 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
R01 MH039683 / MH / NIMH NIH HHS / United States
R01 MH097104 / MH / NIMH NIH HHS / United States
MH115045 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
I01 BX002774 / BX / BLRD VA / United States
BX002774 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / International
NS098505 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / International
NS110355 / / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) / International
I01 BX004500 / BX / BLRD VA / United States
IK2 BX004905 / BX / BLRD VA / United States
HL007901 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / International
HL095491 / / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) / International
R21 NS110355 / NS / NINDS NIH HHS / United States
IK2 BX002130 / BX / BLRD VA / United States
I01 BX001356 / BX / BLRD VA / United States
T32 HL007901 / HL / NHLBI NIH HHS / United States
BX001356 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / International
R01 NS098505 / NS / NINDS NIH HHS / United States
BX002130 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) / International
MH039683 / / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) / International
R01 MH115045 / MH / NIMH NIH HHS / United States
R01 HG005827 / HG / NHGRI NIH HHS / United States
HG005827 / / U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) / International
P01 HL095491 / HL / NHLBI NIH HHS / United States