Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice.
Proc Natl Acad Sci U S A
; 117(8): 4392-4399, 2020 02 25.
Article
in En
| MEDLINE
| ID: mdl-32041882
ABSTRACT
The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bipolar Disorder
/
Synaptotagmins
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Adult
/
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2020
Type:
Article
Affiliation country:
China