The role of glial activation and synaptic transmission in transsynaptic neurodegeneration

<p dir="ltr">Transsynaptic degeneration (TSD) is a prominent feature of many neurodegenerative diseases, involving the spread of damage from the initial site to connected regions of the central nervous system (CNS). This phenomenon is particularly well-documented in the context of the visual pathway. This thesis aims to determine the influence of glial activity and demyelination on TSD, and to assess the role of synaptic transmission in TSD and whether the spread of damage is independent of this. To explore the impact of glial activity and demyelination, we utilized the cuprizone (CZ) diet model in C57B mice. This model induces spontaneous de/remyelination and chronic demyelination, mimicking aspects of neurodegenerative processes. By combining CZ treatment with optic nerve crush (ONC) injury, we assessed the influence of demyelination on TSD. Visual evoked potentials (VEPs) were employed to monitor functional and structural changes in the visual pathway under these conditions. Our findings revealed that increased glial and apoptotic markers were evident in contralateral higher visual centres of ONC eyes with pronounced demyelination compared to controls. This underscores the neuroprotective role of myelin in mitigating TSD progression. Next, we investigated the role of neurotransmission in TSD using an adeno-associated viral (AAV) vector containing tetanus toxin light chain (TeNT) to block synaptic transmission at the retina. Despite synaptic blockage, both TeNT and control eyes subjected to ONC exhibited reduced VEP amplitudes compared to uninjured controls. Interestingly, glial and apoptotic marker expression in the ONC contralateral dorsal lateral geniculate nucleus (dLGN) was similar between TeNT and control eyes, indicating that blocking synaptic transmission alone did not prevent TSD. The findings of this thesis have clarified that the involvement of synaptic transmission plays little part, if any, in TSD progression, while an absence of adequate myelination appears to aggravate it. Glial cells are crucial components in both mitigation and propagation of TSD, making them prime targets for therapeutic development.</p>