Monday, April 29, 2024
4/29/2024
An important question in the field of multiple sclerosis (MS) is whether myelin/axonal damage in the white matter facilitates neuronal cell body loss in the gray matter, or results from two independent processes. Neurodegeneration underlies progressive decline in MS for which there is no remedy, highlighting the significance of elucidating its mechanisms. To address this question, we utilized the visual system, where all myelinated axons in the optic nerve arise from retinal ganglion cells (RGCs). In patients with MS, RGC loss and retinal thinning correlate with whole-brain and gray matter atrophy. Therefore, visual assessments may be a sensitive biomarker for neurodegeneration. Furthermore, the visual system is being used to determine the efficacy of new clinical trial drugs to treat MS. Preliminary data presented in this proposal demonstrate that blocking AMPA-type glutamate receptor (AMPAR) signaling in mature oligodendrocytes (OLs) prevents axonal damage in the optic nerve and inhibits retinal ganglion cell loss in experimental autoimmune encephalomyelitis (EAE). Glutamate dysregulation is implicated in multiple sclerosis (MS), but whether excitotoxic mechanisms specific to OLs contribute to myelin degradation and impact axonal injury has not been explored. Elevated levels of glutamate are detected prior to the appearance of new T2-visible white matter lesions implicating glutamate as an important excitotoxin in patients with MS. We previously reported that MOG-reactive T cells provoke microglia to release glutamate from the system xc- transporter, promoting myelin degradation during autoimmune demyelination. Here, we show that selective deletion of AMPAR function on mature OLs diminished the clinical symptoms of EAE, attenuated myelin and axonal loss in the optic nerve, and inhibited RGC loss. Therefore, we hypothesize that reducing AMPAR-signaling in OLs prevents demyelination and/or promotes remyelination, resulting in preservation of the underlying axon and its neuronal soma. These studies will utilize inducible OL-specific deletion of AMPARs in chronic and relapsing-remitting autoimmune inflammatory (EAE) to explore the impact on axon integrity and ultimately RGC health. Effects of deleting AMPARs on ionotropic glutamate receptor function will be determined by Ca2+ imaging and mechanisms of cell death as well as changes in proliferation and differentiation that may promote remyelination. Axon viability will be assessed by confocal 3D reconstruction, electron microscopy, and mitochondrial trafficking and morphology using transgenic mice that express fluorescent mitochondria. Changes in OL number and maturation state will be tracked with the genetic fluorescent reporter tdTomato, to determine the fate of newly proliferated OL progenitor cells separately from pre-existing myelin. Furthermore, pathological assessments of the retina will be evaluated in light of longitudinal functional visual assessments (visual evoked potentials and electroretinograms) and longitudinal structural visual imaging (optical coherence tomography) to investigate how inducible deletion of AMPAR function in OLs modulates retinal function at key time points in demyelinating diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
