MITOCHONDRIAL DYNAMICS ARE SELECTIVELY ALTERED IN PARVALBUMIN NEURONS DURING GREY MATTER DEMYELINATION

The quest for effective neuroprotective treatments in multiple sclerosis (MS) is important to avoid neurodegeneration. Demyelination of cortical grey matter in MS correlates with worsening disability, and some neuronal types, such as parvalbumin interneurons (PV), are particularly vulnerable to neurodegeneration after demyelination. These neurons are heavily myelinated, highly metabolically active and rely on mitochondrial oxidative phosphorylation for their function. Here, we hypothesised that unique mitochondrial changes in PV neurons in response to demyelination may underlie their selective vulnerability, and that manipulating these may help identify potential neuroprotection targets. To test this hypothesis, we used a mouse model of focal subpial grey matter demyelination. During early demyelination, using high-resolution 3D confocal microscopy, we identified increased mitochondrial volume and branching in demyelinated PV neurons suggesting mitochondrial fusion, but not in other neurons. In these cells, we also found increased mitochondrial fusion protein expression and downregulation of fission proteins, consistent with an early neuroprotective mitochondrial response. In contrast, in human post-mortem MS grey matter lesions, surviving PV neurons displayed reduced mitochondrial size and a shift toward fission, suggesting a temporal loss of this protective response in chronic demyelination. To alter mitochondrial dynamics, we manipulated fission–fusion balance locally with small-molecule inhibitors and cell-type–selectively using a Cre-dependent AAV-Mfn2 approach in PV-Cre mice to test whether these interventions can rescue PV neuron loss. Overall, our findings suggest that temporal changes in mitochondrial dynamics contribute to the selective vulnerability of PV neurons in progressive MS, and that manipulation of these pathways may enhance neuronal survival.