We made the interesting observation from a previous study with mice that cannot produce histamine, a molecule found in the body. These mice showed unusual changes in the outer part of the retina, which is similar to what happens in certain eye diseases like Retinitis Pigmentosa and Leber’s Congenital Amaurosis. Based on this observation, we came up with a hypothesis that histamine might play a role in the development and health of the retina, especially the photoreceptors.
The aim of this project was to study how histamine affects the development of photoreceptors and what happens when there is a lack of histamine in the body. By understanding the role of histamine in photoreceptor development and the consequences of its deficiency, we hope to gain valuable insights into the mechanisms behind retinal diseases and potentially discover new ways to treat them.
Project Results and Impact
Our experiments focused on studying mice that cannot produce histamine (HDC-KO mice) and their retinal development. Here are the key findings and their impact:
- Disruptions in the retina: We observed that early disruptions in the retina, such as displaced photoreceptors, occurred in HDC-KO mice shortly after birth. As the mice grew, these disruptions became more severe, leading to the loss of photoreceptors in large regions of the retina in adulthood.
- Outer Limiting Membrane (OLM) disruption: We discovered that the OLM, an important structure in the outer retina, was disrupted in HDC-KO mice. The OLM maintains the proper orientation of photoreceptors and their close relationship with the Retinal Pigment Epithelium, which is crucial for photoreceptor survival. Mutations in genes associated with OLM proteins have been linked to photoreceptor death in human diseases like Leber’s Congenital Amaurosis.
- Histamine’s role: We found that histamine, a molecule expressed in the photoreceptor layer, plays a role in maintaining the expression of adherens junctional proteins in Müller cells. These proteins are essential for the proper functioning of the OLM, photoreceptor polarity, and viability.
Impact for retinal degeneration:
- Our findings provide valuable knowledge about retinal degenerations caused by mutations affecting the OLM, a crucial region in maintaining photoreceptor health. This expands our understanding beyond mutations in rod-associated proteins like rhodopsin.
- Understanding the mechanisms by which defects in the OLM lead to photoreceptor degeneration is crucial for developing treatments for severe inherited retinal degenerations such as Leber Congenital Amaurosis and autosomal recessive Retinitis Pigmentosa.
- Our discovery regarding the role of histamine in regulating Müller cell expression of adherens junctional proteins is a significant step towards understanding the pathogenesis of these unique forms of retinal degeneration. This knowledge opens up possibilities for developing future treatments and interventions.
Overall, our study sheds light on the importance of histamine and the OLM in retinal health, providing a foundation for further research and potential therapeutic strategies for retinal degenerative diseases.
Dr Ursula Greferath
University of Melbourne