AI Article Synopsis
- CACNA1I is a gene associated with schizophrenia that affects the function of the Ca3.3 calcium channel, and a specific mutation (R1346H) was found to impair its function in previous research.
- Researchers created mouse models with the R1346H mutation and ones lacking Ca3.3 to study changes in brain cell activity, particularly in the thalamic reticular nucleus (TRN), where this channel is prevalent.
- The study revealed that the R1346H mutation led to significant disruptions in sleep spindle patterns during NREM sleep, suggesting this mutation can serve as a model for understanding sleep anomalies in schizophrenia and evaluating potential treatments.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026444 | PMC |
| http://dx.doi.org/10.1038/s41398-020-0685-1 | DOI Listing |
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