Role of Astrocytes in Brain Physiology and Neurologic Disease
Astrocytes are the most abundant non-neuronal cells in the central nervous system (CNS). Despite astrocytes have been recognized as the essential component in functional synapses and actively modulate various physiological processes in the brain, how astrocytes acquire their unique morphology and functions during development remains essentially unknown. Potential astrocyte subtypes in the mammalian central nervous system also remain uncharacterized. Lack of this knowledge has become a significant hurdle in understanding astrocyte dysfunction in neurologic disorders/diseases. Astrocytes have been clearly implicated in several neurological diseases/disorders, significantly influencing the progression of these diseases. My lab is currently focusing on the regulation of astroglial glutamate transporter (EAAT2/GLT1) expression; Neuron-dependent regulation of astrocyte maturation during development and in adult brain; Characterization of the identity/molecular property of reactive astrocytes in neurological diseases/injuries; Molecular mechanisms of astrocyte dysfunction in pathogenesis of neurodevelopmental disorders (fragile X syndrome) and motor neuron degeneration (amyotrophic lateral sclerosis). Research in my lab will provide novel knowledge about the EAAT2/GLT1 regulation and astrocyte maturation, as well as unveil the mechanisms for the pathological alterations of neuron and astrocyte interaction in neurological disease, Ultimately, it will help develop astroglia-based neuroprotective strategies for these diseases/disorders.
Molecular mechanisms of astrocyte maturation and function
Despite the importance of astrocytes in the CNS, how they become developmentally mature, especially the acquisition of their unique morphology and interaction with synapses/vasculatures and induction of astroglial specific functional genes, has remained essentially unknown. My lab is interested in the molecular mechanisms how astrocytes become functionally mature during postnatal development, especially the role of neuronal signals in astrocyte maturation. To answer these questions, we employ cutting-edge molecular (TRAP technique), imaging (in vivo astrocyte morphology analysis), genetic (Cre-loxP conditional knock-out mice), and electrophysiological (astrocyte patch and dye-filling) approaches, complemented with in vitro primary astrocyte and neuron co-cultures.
Figure 1. Uniquely ramified cortical astrocyte morphology.
MicroRNA-dependent regulation of astroglial glutamate transporter EAAT2/GLT1
Astroglial excitatory amino acid transporter 2 (EAAT2, rodent analog GLT1) is one of the most enriched brain proteins, playing a critical and irreplaceable role in safeguarding extracellular glutamate levels in the mammalian CNS. Low levels of extracellular glutamate greatly facilitate the proper signal transmission at synapses and prevent glutamate-induced excitotoxicity. Expression of EAAT2/GLT1 is highly dynamic under different conditions, however, the regulation mechanisms of EAAT2/GLT1 is largely unknown. My lab is interested in neuron-dependent regulation of astroglial EAAT2/GLT1 expression and the mechanisms of selective expression of EAAT2/GLT1 in astrocytes. We have recently characterized a neuronal exosome-mediated miRNA pathway that regulates translational expression of GLT1 in astrocytes.
Figure 2. Neuronal exosomal miRNA-dependent regulation of EAAT2/GLT1 in astrocytes.
Astrocyte dysfunction and pathogenesis of Fragile X Syndrome (FXS)
Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder, caused by the loss of function of FMRP. FXS closely resembles autistic syndrome. Functions of FMRP in glial cells remain largely unknown. In addition, little is known about the non-cell autonomous pathogenic mechanisms, -the role of astroglia in the pathogenesis of FXS. We will employ a combination of molecular (TRAP-based profiling), genetic (FMRP conditional knock-out), biochemical, and electrophysiological approaches to investigate the role of astrocytes in pathogenesis of FXS. We have recently demonstrated a unique activation role of FMRP in regulating protein expression in astrocytes. We found that astroglial glutamate transporter subtype GLT1 and glutamate uptake is significantly reduced in cortex of the fragile X mice (fmr1-/- mice), which may contribute to enhanced cortical neuronal excitability.
Figure 3. Expression of FMRP in mature cortical astrocytes in vivo.