RÉSUMÉ
Methyl-CpG binding protein 2 (MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing. Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, heightened anxiety, epilepsy, autistic phenotypes, and early death. Reversal of the abnormal phenotypes in adult mice with MECP2 duplication (MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated. However, whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown. Here, we found that MECP2-TG mice showed a significant social recognition deficit, and were prone to display aversive-like behaviors, including heightened anxiety-like behaviors and a fear generalization phenotype. In addition, reduced locomotor activity was observed in MECP2-TG mice. However, appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice. Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors. We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex (mPFC) and bed nuclei of the stria terminalis (BST) of adult MECP2-TG mice, and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit. These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice, and provide new insight into potential therapies for MECP2 duplication syndrome.
RÉSUMÉ
Objective To explore the regulation of berberine on the expressions of CDK4 and cyclin D1 in the neurons after the focal cerebral ischemia/reperfusion and the potential protective mechanism of berberine to neurons. Methods Fifty male Wistar rats were randomly divided into berberine-treated group (n=15), normal control group (n=5), sham-operated group (n=15) and vehicle-treated group (n=15). The model of focal cerebral ischemia was constructed using middle cerebral artery occlusion (MCAO) method. At 1, 3, 5 d after 1 hour ofischemia, the expressions and distributions of Bcl-2, cyclin D1 and CDK4 in each group were detected by immunohistochemistry, and morphological changes of brain were observed by HE staining. Results HE staining showed that in the berberine-treated group, the number of neurons was decreased less than that in vehicle-treated group at reperfusion 3 and 5 d. For the result of immunohistochemistry for Bcl-2 positive neurons, there was no obvious difference between berberine-treated group and vehicle-treated group at reperfusion 1 d (P>0.05),however, the number of the Bcl-2 positive cells in berberine-treated group at reperfusion 3 and 5 was significantly increased (P<0.01), and the numbers of cyclin D 1 and CDK4 positive cells were decreased as compared with those in the vehicle-treated group. Conclusions In the rat focal ischemia model,berberine can inhibit the neural expressions of cyclin D1 and CDK4 in the penumbra, that indicates berberine may have the potential of neural protection. The possible mechanism is that berberine can decrease the neural expression ofcyclin D1 and prevent it from entering the nucleus, thereby blocking the cascade reaction and suppressing the apoptosis mediated by cyclin D1.