Annie Lin
Research Mentor: Not Available Not Available
Mentor Department: Not Available, Not Available
Author(s): Not Available
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type: Poster 7
Abstract
Multiple sclerosis (MS) is a chronic neurologic disease of the central nervous system characterized by progressive disability, inflammatory demyelination, and neurodegeneration. Retinal ganglion cells (RGCs) are targeted by many MS pathologies, including demyelination, axonal degeneration, synapse loss, and cell death, corresponding to visual deficits frequently experienced by people with MS. Neuronal hyperexcitability occurs in MS and MS-relevant animal models and can contribute to neurodegeneration, though it is still unknown whether RGC hyperexcitability directly drives RGC pathologies. In this study, we implement a system utilizing adeno-associated virus serotype 2 (AAV2)-delivered Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to specifically increase and decrease RGC activity in a minimally invasive manner, allowing us to investigate how RGC activity regulates RGC pathologies in the experimental autoimmune encephalomyelitis (EAE) mouse model, the most common MS-relevant preclinical model. Initial validation of the cre-dependent AAV2-packaged excitatory and inhibitory DREADDs delivered via intravitreal injections in VGluT2cre (+/+) mice shows high transduction efficiency specific to RGCs, as VGluT2 expression is restricted to RGCs in the eye. Furthermore, no induction of RGC cell death following acute DREADD activation with the specific ligand clozapine N-oxide (CNO) is shown. These findings are recapitulated when using the AAV2-DREADD system in the EAE model and treating chronically with CNO delivered via drinking water for four consecutive days after EAE onset, indicating that modulating RGC activity in early phases of disease does not induce RGC cell death. Thus, our current focus is on utilizing this approach to assess how neuronal activity regulates RGC demyelination, axonal degeneration, and synapse loss in demyelinating disease.
