Astrocytes are now recognized as active components of mature synapses;they structurally ensheath synapses and modulate neurotransmission in the central nervous system (CNS). Astrocyte dysfunction has been implicated in various neurological disorders and has been shown to actively modulate disease progression. Although astrocytes undergo a developmental maturation process in which subtypes form unique and elaborate morphologies and express overlapping but distinct molecular signatures, it is unknown how astrocyte heterogeneity arises during development of the CNS and how astrocyte development is regulated, in part because of a lack of appropriate tools for such studies. We propose to use integrated molecular and genetic approaches in Drosophila and mouse to define factors that distinguish astrocyte subtypes and regulate their developmental maturation. In particular, this project will focus on these aims: 1) Molecularly define astrocyte subtypes within the cortex and in different CNS regions using FACS and TRAP approaches;2) Perform dEAAT1-based genetic screens to identify regulators of astrocyte development;3) Develop new cre recombinase mice for studying astrocyte heterogeneity and function in vivo. We have generated a large amount of preliminary data demonstrating feasibility for the three aims summarized above. By characterizing molecular signatures of astrocyte subtypes in the CNS and identifying regulators of astrocyte development, this project will provide markers for astrocyte subtypes in the cortex and novel insights about how astrocyte maturation occurs. The development of a new cre recombinase driver mouse line will facilitate the selective deletion/activation of genes in astrocytes of the cortex, a region for which an existing astrocyte cre driver line is not very effective. Knowledge of astrocyte heterogeneity and new tools for studying it are critical for understanding how astrocytes become dysfunctional and how distinct classes of astrocytes contribute to the pathogenesis of psychiatric disorders.
This project aims to define molecules that distinguish astrocyte subtypes and regulate astrocyte developmental maturation. It will also generate new mouse strains that will permit efficient and selective gene manipulation in different populations of astrocytes. The new knowledge and tools arising from this research will be valuable for further studies of astrocyte heterogeneity and how dysfunction of this cell type contributes to psychiatric disorders.
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|Andresen, Lauren; Hampton, David; Taylor-Weiner, Amaro et al. (2014) Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation. Neurobiol Dis 71:305-16|
|Kawamata, Hibiki; Ng, Seng Kah; Diaz, Natalia et al. (2014) Abnormal intracellular calcium signaling and SNARE-dependent exocytosis contributes to SOD1G93A astrocyte-mediated toxicity in amyotrophic lateral sclerosis. J Neurosci 34:2331-48|
|Higashimori, Haruki; Morel, Lydie; Huth, James et al. (2013) Astroglial FMRP-dependent translational down-regulation of mGluR5 underlies glutamate transporter GLT1 dysregulation in the fragile X mouse. Hum Mol Genet 22:2041-54|
|Yang, Yongjie; Higashimori, Haruki; Morel, Lydie (2013) Developmental maturation of astrocytes and pathogenesis of neurodevelopmental disorders. J Neurodev Disord 5:22|
|Morel, Lydie; Regan, Melissa; Higashimori, Haruki et al. (2013) Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem 288:7105-16|