Astrocytes are essential for the maintenance of homeostasis within the central nervous system (CNS). These cells produce thrombospondins (TSPs), large oligomeric matricellular proteins with important roles in cell attachment, cell migration, cytoskeletal dynamics and angiogenesis. TSP-1 and TSP-2 have also recently been identified as the main astrocyte-derived factors that promote excitatory synapse formation in vitro and during development in vivo. This activity has been mapped to their epidermal growth factor-like repeats, via binding to the neuronal a2d-1 voltage-gated calcium channel that is also a receptor for the drug, gabapentin (GBP). GBP potently inhibits TSP-mediated synapse formation in vitro and during development in vivo. While TSP levels generally decline in the adult CNS, we find measurable amounts of TSP-1 in the spinal cords of normal weanling mice. Furthermore, spinal cord TSP-1 levels fall rapidly and then recover in parallel to the appearance and disappearance of hind limb paralysis during relapsing experimental autoimmune encephalomyelitis (EAE), an established rodent model of the human demyelinating disease, multiple sclerosis (MS). We and others have shown that reversible synaptic pathology can be found in the lumbar spinal cords of mice with relapsing EAE, and we find that systemic administration of GBP to animals with EAE starting at peak paralysis, when spinal cord TSP-1 levels are at their nadir and just beginning to recover, significantly delays both clinical improvement and the reestablishment of motor synapses in lumbar spinal grey matter. Taken together, these findings lead us to hypothesize that astrocytes produce TSP-1 in the adult spinal cord to maintain excitatory synapses in the motor pathway, but the local inflammatory milieu during relapsing EAE causes this mediator to become dysregulated resulting in transient synaptic changes and reversible hind limb paralysis. If confirmed, this would make astrocytes central contributors to the reversible neurological deficits that typify animal CNS demyelinating diseases, and by extension, novel targets for therapeutic intervention in humans. Here, the following aims are proposed: 1) To confirm the importance of astrocyte-derived TSP- 1/TSP-2 signaling through neuronal a2d-1 voltage-gated calcium channels in mediating the reversible paralysis of relapsing EAE by acting on excitatory synapses in motor pathways of the spinal cord, and 2) To characterize the mechanisms that cause astrocytes to down-regulate TSP-1 expression in vitro and in the spinal cord during EAE in vivo, and determine the factors responsible for the return of spinal cord TSP-1 expression and clinical recovery as EAE remission occurs. These studies will clarify novel cellular and molecular mechanisms underlying reversible neurological deficits in an established animal model of CNS demyelinating disease. Since clinical relapses beget chronic disease progression in human MS, it is essential to better understand these reversible events and to develop novel approaches that block them. Current MS therapies target the inflammatory response, but none as of yet directly intervene at either the neuronal or the glial cell level.
These studies will clarify novel mechanisms underlying the development of reversible paralysis that occurs in a well-established animal model of the human demyelinating disease, relapsing-remitting multiple sclerosis (MS). Since temporary clinical relapses lead to chronic irreversible disease progression in human MS, it is essential to better understand these events and to develop novel treatment approaches that block them. Current MS therapies target the immune response, but none as of yet can directly intervene at the level of nerve cells or their connections as we intend to do.
|Huber, Amanda K; Irani, David N (2015) Targeting CXCL13 During Neuroinflammation. Adv Neuroimmune Biol 6:1-8|
|Blakely, Pennelope K; Hussain, Shabbir; Carlin, Lindsey E et al. (2015) Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis. Front Neurosci 9:344|