ABSTRACT
Mechanistic target of rapamycin (mTOR) signaling governs important physiological and pathological processes key to cellular life. Loss of mTOR negative regulators and subsequent over-activation of mTOR signaling are major causes underlying epileptic encephalopathy. Our previous studies showed that UBTOR/KIAA1024/MINAR1 acts as a negative regulator of mTOR signaling, but whether UBTOR plays a role in neurological diseases remains largely unknown. We therefore examined a zebrafish model and found that ubtor disruption caused increased spontaneous embryonic movement and neuronal activity in spinal interneurons, as well as the expected hyperactivation of mTOR signaling in early zebrafish embryos. In addition, mutant ubtor larvae showed increased sensitivity to the convulsant pentylenetetrazol, and both the motor activity and the neuronal activity were up-regulated. These phenotypic abnormalities in zebrafish embryos and larvae were rescued by treatment with the mTORC1 inhibitor rapamycin. Taken together, our findings show that ubtor regulates motor hyperactivity and epilepsy-like behaviors by elevating neuronal activity and activating mTOR signaling.
ABSTRACT
Mechanistic target of rapamycin (mTOR) signaling governs important physiological and pathological processes key to cellular life. Loss of mTOR negative regulators and subsequent over-activation of mTOR signaling are major causes underlying epileptic encephalopathy. Our previous studies showed that UBTOR/KIAA1024/MINAR1 acts as a negative regulator of mTOR signaling, but whether UBTOR plays a role in neurological diseases remains largely unknown. We therefore examined a zebrafish model and found that ubtor disruption caused increased spontaneous embryonic movement and neuronal activity in spinal interneurons, as well as the expected hyperactivation of mTOR signaling in early zebrafish embryos. In addition, mutant ubtor larvae showed increased sensitivity to the convulsant pentylenetetrazol, and both the motor activity and the neuronal activity were up-regulated. These phenotypic abnormalities in zebrafish embryos and larvae were rescued by treatment with the mTORC1 inhibitor rapamycin. Taken together, our findings show that ubtor regulates motor hyperactivity and epilepsy-like behaviors by elevating neuronal activity and activating mTOR signaling.
Subject(s)
Animals , Hyperkinesis/genetics , Mutation/genetics , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Zebrafish/metabolismABSTRACT
@#Objective To investigate the effects of estrogen on brain derived neurotrophic factor (BDNF) and neuropeptide Y (NPY) levels in cerebellar cortex of ovariectomized rats. Methods 24 female Wistar rats were randomly divided into three groups: intact (INT) group, ovariectomized (OVX) group, and OVX+estrogen 0.5 mg/kg every day group (E group). Radioimmunoassay (RIA) was used to measure the estrogen content in plasma, and the levels of BDNF and NPY were measured with Immunohistochemistry. Results Compared with the INT group, the plasma estrogen level significantly reduced in OVX group (P<0.001). However, the plasma estrogen level was higher in the E group than that in the OVX group (P<0.001). The BDNF and NPY presented in the Purkinje cell layer,and BDNF also distributed in the molecular layer and granular layer. Compared with that in the INT group, BDNF and NPY positive cells markedly decreased in OVX group, with slight cytosol staining in the cerebellar cortex (P<0.001). The BDNF and NPY positive neurons increased in E group compared with that in the OVX group (P<0.001). Conclusion Estrogen can increase the BDNF and NPY levels in cerebellar cortex of female rats, which may protect the structure and function of cerebellar neurons.
ABSTRACT
@#Estrogen is an important active endogenous substance which is needed by female to sustain normal psychological and physiological function.Studies have demonstrated that estrogen has an extensive effect on the central nervous system.This review explained the relation between estrogen and learning on a few aspects such as neurobiochemistry,neurophysiology,neuroanatomy,signal transduction and so on.