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Haruhisa Okawa, Luca Della Santina, Greg Schwartz, Daniel Kerschensteiner, Fred Rieke, Rachel Wong; Distinct Roles Of Activity-Dependent And Independent Mechanisms In Regulating The Bipolar Cell Inputs Onto Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4562.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cell (RGC) responses are shaped by the types of bipolar cells (BCs) providing input and the number of synapses made by a given BC. How BC - RGC synaptic connectivity patterns are established during development is not well understood. We investigated the role of activity-dependent and independent mechanisms in regulating BC connectivity with A-type ON RGCs (A-RGC) in the mouse retina. Our previous studies determining BC input types onto A-RGCs form the basis for this work.
To understand how activity imbalance among BCs locally influences their connectivity, we generated transgenic mice in which tetanus toxin light chain (TeNT) is sparsely expressed by the population of ON BCs. To probe the role of activity-independent mechanisms, we generated mice expressing the attenuated form of diphtheria toxin (DTA) in all ON BCs. Excitatory postsynaptic sites on A-RGC dendrites were biolistically labeled by fluorescent protein-tagged PSD95. Light responses of A-RGCs were recorded using patch-clamp techniques.
The number of synapses formed between type 6 (T6) BCs and A-RGCs were selectively reduced in TeNT-expressing (inactive) BCs. Neighboring active T6 BCs did not expand their axon territory or alter their synapses with the A-RGC. In DTA-expressing mice, the majority of T6 BCs were ablated whereas other ON BC types were less affected. Surviving T6 BCs expanded their axon territories and increased the number of synapses made onto A-RGCs. Surprisingly, despite the presence of other ON BC types, ~80 % of labeled A-RGCs projected dendrites to the OFF layer, where they primarily contacted T2 BCs. These ectopic synapses were functional because A-RGCs showed ON-OFF light responses. Such ectopic dendrites were not observed when all ON BCs express TeNT (Kerschensteiner et al, 2009).
Activity-dependent and independent mechanisms together regulate the number of synapses that individual T6 BCs form with A-RGCs. Activity-independent mechanisms regulate BC connectivity by limiting their axon territory size, presumably via homotypic interactions. If the axon territory is unchanged, BCs can still alter their number of synapses with the RGC on a cell by cell basis in an activity-dependent manner. Moreover, the absence of a major BC input type can cause the RGC dendrites to extend and make novel contact with other specific BC types.
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