SeanJMillerUnraveling astroglia heterogeneity in health and disease

My research focuses on astroglia heterogeneity in the adult central nervous system (CNS). Astroglia are the most abundant cell type in the CNS, playing essential roles in maintaining homeostasis. Important functions of astroglia include regulation of neurotransmitter recycling, elimination and generation of neuronal synapses, immune-modulation, and support of the blood-brain-barrier. Historically, astroglia have been categorized into two groups based on their morphological depictions and gross anatomical localization. This includes protoplasmic astroglia of the grey matter and fibrous astroglia of the white matter. More recently, accumulating evidence in development and adulthood has suggested that astroglia display a high level of heterogeneity in order to support their physiological niche. To better understand these different subtypes, we generated a novel transgenic mouse model that selectively and robustly labels an astroglia subpopulation in cortical layers II/II and V, and also in the spinal cord with tdTomato-fluorescence. After extensive analyses, we have shown that these astroglia subtypes are also present in the human cerebral cortex. More importantly, we now know that these astroglia interact with neighboring neurons to promote dendritic branching and spine density by the release of neuron-modulating polypeptides. In neurological diseases such as psychosis and neurodegeneration we have also shown that these astroglia are greatly affected in areas of neuronal death and functional deficits. This is among one of the first studies of its kind to exploit a unique astroglia subtype in different neurological disorders and provides us with a potentially new avenue for cell-specific therapeutics.

Recent Publications

  • Veeraraghavalu K.*, Zhang C.*, Miller S.*, et al. A Role for RXR agonists in reducing A-Beta burden revisited: no evidence that Bexarotene alters A-Beta Levels or deposition in Vivo. Published in Science, 2013; 349(924):1235505.
  • Miller S.J., Philips T., Daigle G. et al. Moleculary defined astroglia subtype regulates layer V cortical neurons in Norrie disease. In resubmission to Science.
  • Raven F.*, Ward J.F.*, Katarzyna M., et al. Soluble gamma-secretase modulators attenuate Alzheimer’s beta-amyloid pathology and induce conformational changes in presenilin 1. In submission to eLife.
  • Miller S.J., Zhang P., Glatzer J., Rothstein J.D. Astroglial transcriptome dysregulation in early disease of an ALS mutant SOD1 mouse model. Published in J. Neurogenetics, 2016; DOI: 10.1080/01677063.2016.1260128.
  • Miller S.J., Rothstein J.D. Astroglia in thick tissue with super resolution and cellular reconstruction. Published in PLoS ONE, 2016; 11(8): e0160391.
  • Miller S.J., Rothstein J.D. 3D printed generated tissue iMolds for cleared tissue using single- and multi-photon microscopy for deep tissue evaluation. In Press in Biological Procedures Online.
  • Daigle J.G., Miller S.J., Sattler R. Rothstein J.D. An update on c9orf72 from neurons to neuroglia. In preparation.
  • Zhang K.*, Donnelly C.*, Haeusler A., et al. The c9orf72 repeat expansion disrupts nucleocytoplasmic transport. Published in the Nature, 2015; 525:56-61.
  • Vorobyeva A., Lee R.*, Miller S.*, Kandelwal P., et al. Cyclopamine modulates Gamma-Secretase mediated cleavage of Amyloid Precursor Protein by altering subcellular trafficking. Published in the Journal of Biological Chemistry, 2014; 289(48):33258-74.
  • Utreja S., Miller S.J., Saunders A.J. Calcineurin overexpression regulates APP metabolism. Published in Advances in Alzheimer’s Disease, 2013; 2(3):109-116.
  • Chakraborty R.,Vepuri V., Mhatre S., Paddock B., Miller S., et al. Characterization of a Drosophila Alzheimer’s Disease model: pharmacological rescue of cognitive defects. Published in PLoS ONE, 2011; 6(6): e20799.