Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice.

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.

CACNB2 rs11013860 polymorphism correlates of prefrontal cortex thickness in bipolar patients with first-episode mania.

BACKGROUND: The ß2 subunit of the voltage-gated l-type calcium channel gene(CACNB2) rs11013860 polymorphism is a putative genetic susceptibility marker for bipolar disorder (BD). However, the neural effects of CACNB2 rs11013860 in BD are largely unknown. METHODS: Forty-six bipolar patients with first-episode mania and eighty-three healthy controls (HC) were genotyped for CACNB2 rs11013860 and were scanned with a 3.0 Tesla structural magnetic resonance imaging system to measure cortical thickness of prefrontal cortex (PFC) components (superior frontal cortex, orbitofrontal cortex, middle and inferior frontal gyri). RESULTS: Cortical thickness was thinner in patients on all PFC measurements compared to HC (p < 0.050). Moreover, we found a significant interaction between CACNB2 genotype and diagnosis for the right superior frontal cortical thickness (F = 8.190, p = 0.040). Bonferroni corrected post-hoc tests revealed that, in CACNB2 A-allele carriers, patients displayed thinner superior frontal thickness compared to HC (p < 0.001). In patients, CACNB2 A-allele carriers also exhibited reduced superior frontal thickness compared to CACNB2 CC-allele carriers (p = 0.016). LIMITATIONS: Lithium treatment may influence our results, and the sample size in our study is relatively small. CONCLUSIONS: Our results suggest that the CACNB2 rs11013860 might impact PFC thickness in patients with first-episode mania. These findings provide evidence to support CACNB2 rs11013860 involvement in the emotion-processing neural circuitry abnormality in the early stage of BD, which will ultimately contribute to revealing the link between the variation in calcium channel genes and the neuropathological mechanism of BD.