Wednesday, April 2, 2025
4/2/2025
Investigating Mechanisms of Development in Retinal Direction Selective Circuits - -Project Summary- As neurons grow, their dendrites develop a unique structure and the ability to perform computations that are essential for nervous system function. Research studying dendritic maturation has largely focused on mechanisms that shape the morphology of the cell but understanding how this structural development relates to the functional development of the dendrite is critical. To that end, I propose investigating dendritic development in a model that allows me to measure functional and structural maturation independently: starburst amacrine cells (SACs) in the mouse retina. SACs are axonless interneurons that have radially symmetric dendrites extending out from the soma. Each branch has a primary dendrite proximal to the soma that receives glutamatergic input from bipolar cells, then branches out in the distal regions where neurotransmitter is released at output synapses marked by varicosities. Functionally, each branch acts as a direction of motion detector; varicosities preferentially release neurotransmitters in response to visual stimuli moving away from the soma. Thus, each branch is an independent computational unit that relays directional information to postsynaptic partners. When and how SAC dendrites develop this functional property is unknown, but there is some evidence to suggest it may happen independently of the morphological development of the cell. Thus, I propose to test the hypothesis that distinct mechanisms underlie structural and functional maturation of SAC dendrites. In Aim 1, I will map the time course of both structural and functional development of SACs and determine the extent to which structural maturity predicts functional maturity. In Aim 2, I will use targeted manipulations to identify mechanisms that dictate this developmental timeline. In Aim 2.1 I will test the hypothesis that SAC functional maturation relies on spontaneous activity during development (retinal waves) and an intracellular protein called FRMD7. Mice without retinal waves and mice with mutations in the FRMD7 gene both show deficits in direction selective circuit function that relies on proper SAC function. Additionally, both models lack normal optokinetic reflexes, a phenotype that was shown to arise from faulty retinal direct selective circuits and is shared with human patients who have FRMD7- related nystagmus. Thus, both models are clinically relevant and promising candidates to reveal mechanisms of functional SAC development. FRMD7 is thought to interact with proteins involved in activity-dependent synaptic protein trafficking, and the location of glutamate synapses on SAC dendrites contributes to their direction-selective output. In Aim 2.2, I will use glutamate uncaging to test the hypothesis that disrupting retinal waves and FRMD7 expression is decreasing direction selectivity by interfering with the trafficking of excitatory receptors to their correct location on the SAC dendrite. Together, these experiments provide insight into how dendrites acquire the ability to compute information and contribute to circuit function, as well as elucidating how changes in such developmental mechanisms can lead to circuit dysfunction.
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