Astrocyte research may lead to development of novel and improved treatments of autism/neurodevelopmental disorders
Astrocytes
are star shaped glial cells in CNS (central nervous system) of mammalian brain which
are derived from neural stem cells during early embryogenesis and express the
marker Glial Fibrillary Acidic Protein GFAP. These astrocytes play an important
role in pathogenesis of autism and other neurodevelopmental disorders such as
Rett syndrome and FXS (Fragile X Syndrome) that result from synaptic defects.
Astrocytes can modulate synaptogenesis (by releasing molecular signals such as
thrombospondin/TSP that specifically increases number of excitatory synapses) during
their developmental maturation in CNS and play an active role in synaptic
physiology in the human brain [1]. In
adult CNS astrocytes serve a number of regional functions such as axon guidance,
control blood brain barrier and blood flow, synaptic support (regulation of
synapse function and synaptic remodeling), maintaining brain homeostasis,
regulating neuronal signaling, neuronal migration, protecting neurons from
oxidative damage and determining the fate of endogenous neural precursors. Astrocytes
also remove excess glutamate from extracellular space and supply glutamine to maintain
glutamatergic neurotransmission. Glutamate
transporter dysregulation results in pathogenesis of FXS and other neurodevelopmental
disorders. [2]
As
astrocytes play essential roles in synaptic mechanisms astrocyte dysfunction
contributes to behavioral disorders. Recent research found microglial
activation, high level of GFAP (around 3 folds than normal) and
neuroinflammation in individuals with autism spectrum disorders (ASD) which
results in gliosis, reactive injury and disturbed neuronal migration during
early gestation [3].
Another neurodevelopmental disorder Rett syndrome is characterized by mutation in MECP2 (methyl CpG binding protein 2), or loss of MECP2 gene which plays an important role (can modulate the expression of thousands of genes) in brain cells and astrocytes to provide physical and functional support for neurons [4]. Rett and ASD have some similar symptoms including learning and memory problem, repetitive behavior and lack of social interaction though Rett affects mainly girls and ADS affects boys.
Fragile X syndrome, the most commonly inherited form of mental impairment is caused by glial cell dysfunction and transcriptional silencing of FMRP (Fragile X mentally retarded protein) gene by hypermethylation and CGG nucleotide repetition in FMR1 gene that turns off the gene.
Recent
astrocyte research and development indicates their roles in motor neuron diseases
and emphasize the potential of astrocytes/astroglia as therapeutic targets and
agents in cell replacement therapy. A provocative study at University of
Rochester Medical Center in 2013 found evidence that astrocyte provides
restorative benefits of sleep by expending energy to drive water transport
channels whose pumping action convects cerebrospinal fluid around neurons. They
also found that knocking out the transport channels from astrocytes slows the clearance
of neurotoxic molecules such as beta amyloid peptides deposited in Alzheimers
disease by 65%. In large brain found in autistic and other
psychiatric/neurodevelopmental patients the decreased efficiency of passive
diffusion makes astrocyte driven active transport of toxic molecules crucial to
survival.
Recently Laurie Doering a professor at Mcmaster University in Canada established a link by co-culturing healthy hippocampal neurons (that are responsible for learning and memory) and astrocytes. According to his research, in co-culture healthy hippocampal neurons exhibited delayed dendritic branching (a process of neural network building) and restricted the development of excitatory synapses. His research (for which he received a passion in science award by New England Biolabs) is actively working to identify new astrocyte based factors for the treatment of neuronal dysfunction using molecular, cellular and behavioral approaches. The interaction between astrocyte and secreted molecules from them and neurons leads to study how astrocyte dependent factors and signaling molecules can modulate the structure and physiology of FXS/ASD neurons [5]. A detailed understanding of how astrocytes regulate neural circuit development and their function in brain may lead to discovery of novel therapeutic treatment of ADS/FXS and other neurodevelopmental disorders.
