Astrocytes are the most abundant cell type in the central nervous system (CNS), and recent studies have demonstrated that astrocytes not only play critical roles in the construction of neural circuits during development, but also that astrocyte dysfunction is a key feature of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The progenitor cells that give rise to the distinct subclasses of neurons during development in the spinal cord also generate astrocytes, and recent work has suggested that astrocytes, like neurons, exhibit positional identities dependent upon the progenitor domain from which they originate. These region-specific astrocyte subtypes may have important roles in the development of local spinal circuits, as well as in neurodegenerative diseases in which very specific populations of neurons are affected- motor neurons in the case of ALS. The goal of this proposal is to investigate how the regional identity of astrocytes contributes to the formation of sensory-motor circuits in the mammalian spinal cord, and to the dysfunction of these circuits that occurs in disease. The experiments described here will make use of novel transgenic tools in mice to probe regional populations of astrocytes in the spinal cord in order to analyze these populations on a gene expression level. Gene profiling experiments will be performed on astrocytes from anatomically distinct regions of wild type mice, as well as from ALS mouse models harboring the well- characterized mutant SOD1 transgene. In addition, a novel in vitro assay for astrocyte secreted factors that influence motor neuron activity will be employed. Finally, an innovative viral tracing strategy will be developed t label subsets of astrocytes that associate with synapses in defined sensory-motor circuits. Collectively, these studies will allow for the functional characterization of diverse astrocyte subtypes in the spinal cord, as well as an understanding of how these cells sculpt the formation and activity of sensory-motor circuits both during development and in disease.
The loss of spinal motor neurons causes severe neurodegenerative disease in humans, including amyotrophic lateral sclerosis (ALS). Although the cause of ALS remains elusive, the dysfunction of astrocytes is hypothesized to play a role. Because astrocytes demonstrate diverse subtypes in the central nervous system, the study of regionally restricted astrocyte subtypes in the spinal cord may yield significant insight into the selective loss of motor neurons in ALS and other neurodegenerative diseases.
