Title: Abnormal Calcium Homeostasis in Rett Syndrome Astrocyte
Legend: (A) Representative GCaMP6s image showing two astrocytes in vivo. The somas and the processes could be clearly identified. Scale bars = 10 μm. (B) Representative ΔF/F0 traces showing the spontaneous intracellular Ca2+ activity in the soma of astrocytes in vivo from wild type and Mecp2 null astrocytes. (C) Quantification of the frequency (left) and the full width at half maximum (FWHM, right) of the astrocytic Ca2+ oscillations in vivo. **p<0.01. (D) The mechanism and consequence of abnormal Ca2+ homeostasis in Mecp2 mutant astrocytes. Elevated expression of TRPC4 in mutant astrocytes leads to enhanced store operated calcium entry, calcium overload in the endoplasmic reticulum and subsequent abnormal intracellular Ca2+ activity. In our mouse model, augmented astrocytic Ca2+ elevations induce Ca2+ dependent glutamate release, excessive activation of extrasynaptic NR2B-containing NMDA receptors on neighboring neurons, and the network hyperexcitability.
Citation: Qiping Dong, Qing Liu , Ronghui Li , Anxin Wang , Qian Bu , Kuan Wang and Qiang Chang. Mechanism and Consequence of Abnormal Calcium Homeostasis in Rett Syndrome Astrocytes. eLife, Mar. 2018.
Abstract: Astrocytes play an important role in Rett syndrome (RTT) disease progression. Although the non-cell-autonomous effect of RTT astrocytes on neurons was documented, cell-autonomous phenotypes and mechanisms within RTT astrocytes are not well understood. We report that spontaneous calcium activity is abnormal in RTT astrocytes in vitro, in situ, and in vivo. Such abnormal calcium activity is mediated by calcium overload in the endoplasmic reticulum caused by abnormal store operated calcium entry, which is in part dependent on elevated expression of TRPC4. Furthermore, the abnormal calcium activity leads to excessive activation of extrasynaptic NMDA receptors (eNMDARs) on neighboring neurons and increased network excitability in Mecp2 knockout mice. Finally, both the abnormal astrocytic calcium activity and the excessive activation of eNMDARs are caused by Mecp2 deletion in astrocytes in vivo. Our findings provide evidence that abnormal calcium homeostasis is a key cell-autonomous phenotype in RTT astrocytes, and reveal its mechanism and consequence.
About the Lab: The long-term goal of the Chang lab is to understand the molecular mechanism underlying DNA methylation-dependent epigenetic regulation of brain functions. His current focus is on the central role of MeCP2 (methyl-CpG binding protein 2), a molecular linker between DNA methylation and chromatin remodeling and transcriptional control, in the development and function of the nervous system. The functional significance of such a molecular linker is highlighted by the fact that mutations in the MECP2 gene cause Rett syndrome (RTT), a debilitating neurodevelopmental disorder that shares many features with autism. His studies include basic research aimed at understanding the function of MeCP2 and translational research aimed at understanding disease pathology and developing effective treatment. These two types of research are tightly interwoven—the need to solve a practical problem in translational research will always influence the direction of basic research; and fundamental mechanisms revealed by basic research will ultimately guide the effort in treating/curing the disease.