The long-term objective of our research is to understand the Ca2+ signaling mechanisms that regulate the development and mature function of the retinal circuitry. The overall objective of the proposed research is to determine the modulatory impact of amyloid proteins on the first synapse in the visual pathway formed between photoreceptors (PRs) and second order neurons, and how this synapse may be disrupted in the context of Alzheimer?s disease (AD). Our focus will be on Cav1.4 Ca2+ channels, which mediate Ca2+ signals needed for the release of neurotransmitters from PR synaptic terminals, and are necessary for maintaining the structure and molecular organization of the PR synapse. In rodent models of AD, Cav1 subtypes related to Cav1.4 are significantly upregulated due to effects of amyloid b (Ab) aggregates that are the pathological hallmark of AD and which are found to accumulate in the retina of mouse models of AD. Ab is derived from processing of amyloid precursor protein (APP). APP and Ab have been shown to cause the downregulation and upregulation, respectively, of Cav1 channels in neurons. Based on these findings, and the retinal and visual phenotypes in AD mutant mouse strains, our central hypothesis is that APP controls the normal presynaptic functions of Cav1.4 in PRs, and that increasing load of Ab leads to upregulation of Cav1.4 and subsequent disruption of PR synapses in the context of AD.
Our specific aims are to: (1) Determine the effect of APP and Ab on the properties of Cav1.4 and (2) Analyze the structural and molecular organization of PR synapses in APP knockout mice and mouse models of AD. The expected outcome of our research is an understanding of how amyloid proteins affect retinal Cav1.4 channels and PR synapses in normal and diseased states of the retina. The broader impact of our research is the identification of pathways that could shed light on visual phenotypes associated with AD and how the retina could be used as a model system in which to study the synaptopathic mechanisms underlying this disease, thus paving the way for novel disease-modifying therapies.
The expected outcome of our research is an understanding of how amyloid proteins affect retinal Cav1.4 channels and photoreceptor synapses in normal and diseased states of the retina. The broader impact of our research is the identification of pathways that could shed light on retinal and visual phenotypes associated with Alzheimer?s disease, and how they could be used as more effective biomarkers of this disease.
| Kerov, Vasily; Laird, Joseph G; Joiner, Mei-Ling et al. (2018) ?2?-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J Neurosci 38:6145-6160 |
| Williams, Brittany; Haeseleer, Françoise; Lee, Amy (2018) Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin. J Gen Physiol 150:1676-1687 |
