Astroglia are essential for the homeostasis and maintenance of the central nervous system (CNS). They display a vast array of roles such as neurotransmitter metabolism, regulation of synaptic neurotransmitter clearance, extracellular ion buffering, neurotrophic release, immune signaling and blood-brain-barrier maintenance. It is not surprising that astroglia in different regions display diverse functions to maintain their environmental niche. Historically, astroglia were placed into two groups based on their neuroanatomical localization and morphological depictions: protoplasmic astroglia of the grey matter and fibrous astroglia of the white matter. Recent evidence has suggested that astroglia consist of different subpopulations, similar to neuronal functional and molecular heterogeneity. Nevertheless, there still remain large gaps in our understanding of these different subtypes due to a lack of molecular markers to identify and study these populations and how these different astrocytes serve to regulate neurons and their synapses. We recently generated a novel transgenic mouse model that selectively and robustly labels a specific astroglia subpopulation in the adult CNS and thru RNA and protein analyses, have learned that these astroglia are highly and selectively enriched in a secreted protein, norrin. A mutated form of norrin is the cause of a rare neurological degenerative disease, Norrie disease. Our preliminary studies strongly suggest that astroglial norrin plays a significant role in the local formation and/or maintenance of local dendrites and spines. We have early data to suggest that this astrocytic norrin regulates neuronal spine density and dendritic branching in cortical layers. Furthermore, our studies suggest that this astrocyte subpopulation is dramatically affected in amyotrophic lateral sclerosis. In collaboration with Jackson Labs, we recently generated a Norrie disease transgenic mouse which can allow us to explore this protein function in vivo and in disease. We plan several approaches to understand the biology of astroglial norrin and how it may alter dendrites/spines as well its contribution to neurodegeneration in ALS and Norrie disease. We propose to: 1) Evaluate the role of cortical astroglial Norrin in regulating neuronal dendrites and spines in vitro and in vivo. These studies will demonstrate the role that Norrin has in regulating neurons, primarily through dendritic and synaptic development and/or maintenance. 2) Determine whether astroglial mutant Norrin is sufficient to alter synaptic development and/or maintenance in vivo. We have first model of Norrie disease, and will test the hypothesis that norrin can rescue this neurodegenerative disease of astroglia. And 3) Investigate the loss of astroglial norrin in contributing to synaptic loss and neurodegeneration in motor neuron disease models and human ALS. These studies will evaluate the contribution of norrin to synaptic injury in several ALS models and human ALS. Taken together, these findings set the stage to study of this newly identified astrocyte subpopulation in both health and disease, including the potential to generate cell astrocyte-specific therapeutics for several neurological disorders.
Relevance to Human Health. Understanding the biology of astroglia and how the regulate neurons and synapses provides a fundamental biology on the brain and has great applicability to human brain disease. Furthermore, several chronic neurological diseases appear to have a strong basis in astroglial dysfunction, and the studies in this grant will further our understand of the role of these cells in ALS/FTD and could provide a powerful approach to mitigate the neural injury astroglia impose on neurons. Importantly, the role of the astroglial protein, norrin could well extend to other dementias where cortical atrophy and neuronal process are damaged such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Norrie disease, a rare cognitive injury in childhood has its basis on this astroglial pathway and the studies sin this proposal will provide important understanding to its pathogenesis, as well as candidate therapies. The convergent study of actual human brain tissue and appropriate animal models provides an unprecedented approach to understand if this new astroglial disease cascade and may open opportunities for new approaches to dementia.
