Functional and structural adaptations to ageing and acute intraocular pressure elevation in mouse retina

© 2021 Pei Ying LeeIn response to stress, neurons undergo a series of adaptations, which include changes to their synapses, dendrites and eventually axons and cell bodies. One might presume that such stress responses help to prevent cell death, providing a window of time where recovery remains possible. As glaucoma is a disease of the ageing, it may be reasonable to suggest that older eyes somehow show poorer adaptations to stress or have reduced intrinsic abilities to detect pressure changes in their environment (e.g., via mechanosensitive channels such as transient receptor potential (TRP) channels), and thus less capacity to recover. Whilst support for these ideas can be gleaned from a range of studies in other systems including the central nervous system, there has been less work in this area in the context of glaucoma. The overarching aim of the thesis is to understand the functional and structural adaptations that occur in normal ageing, and to consider if such age-related changes modify the way that retinal ganglion cells (RGCs) cope with intraocular pressure (IOP) elevation. Using the mouse as a platform, it was possible to show that in normal ageing, there was a relative preservation of ganglion cell function despite an age-related decline in outer retinal responses. Age-related inner retinal functional adaptations were associated with increases in bipolar cell sensitivity to light and changes to RGC dendritic complexity. Ageing was also associated with slower recovery from a short period of controlled IOP elevation. IOP elevation resulted in smaller ON RGCs in both young and older mice. Importantly, analysis of RGC morphology showed that better functional recovery in younger eyes was associated with adaptations in OFF RGC dendrites, which was not observed in older eyes. The absence of RGC morphological adaptations following IOP elevation may account for the delayed recovery in older eyes. Furthermore, better ganglion cell functional recovery in younger eyes was also associated with TRPV4 upregulation in the ganglion cell layer. In contrast, there was TRPV4 downregulation in older eyes. Consistent with the importance of TRPV4 upregulation for recovery, inhibiting TRPV4 further worsened recovery in older eyes. This work advances our understanding of age-related functional and structural adaptations, providing insights into how normal function is maintained in ageing, with potential negative impacts on the capacity for RGCs to recover from IOP elevation