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Jennifer Michelle Noel, Patrick A Scott, Ian Scott Pyle, Kathryn MH Fransen, Nazarul Hasan, Thomas A Ray, Maureen A McCall, Ronald G Gregg; LRIT3 and OPL Synaptic Structure and Function. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2611.
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© ARVO (1962-2015); The Authors (2016-present)
The retina processes light information through parallel ON and OFF pathways. Responses through the ON pathway are initiated by synapses between rod and cone photoreceptors with ON bipolar cells. The human disease, complete congenital stationary night blindness (cCSNB) results from a disruption in signaling within the ON bipolar cell mGluR6 G-protein coupled cascade. Several proteins within this cascade have been identified due to mutations in either humans and/or mice. A new member of the cascade, LRIT3, was recently found mutated within cCSNB patients and a knockout mouse (Zeitz et al., 2013; Neuillé et al., 2014). The function of LRIT3 within the cascade remains unknown. To better understand the role of LRIT3, we examined the structure of the OPL and the function of the RGCs, which represent the culmination of all retinal processing.
We compared the structure of the pre and postsynaptic elements in the OPL of WT and Lrit3-/- mice using a variety of antibodies and with confocal and electron microscopy. We assessed overall retinal function with electroretinograms (ERG) and retinal ganglion cell (RGC) spontaneous and visually evoked activity with multi-electrode array recordings.
The overall laminar structure of the Lrit3-/- retina is similar to WT. Consistent with published results and other cCSNB mouse models, Lrit3-/- mouse dark- and light-adapted ERGs have a normal a-wave, but lack a b-wave. The dendritic terminals of Lrit3-/- ON BCs lack expression of nyctalopin and TRPM1. Lrit3-/- mice significantly differ from other cCSNB mutants. Cone ON BCs lack expression of mGluR6, GPR179 and RGS11, whereas rod BCs maintain expression of these proteins. There are significantly fewer Lrit3-/- cone pedicles, their synaptic architecture is severely altered and expression of PSD95 and PNA is absent. As expected there are no ON responses, but surprisingly very few (~22%) Lrit3-/- RGCs have even OFF responses.
LRIT3 is necessary for expression and localization of nyctalopin and TRPM1 to the ON BC dendrites. Like all other mouse models of cCSNB LRIT3 is critical to signaling in ON BCs, however, unlike all other cCSNB models, cone pedicle structure is disrupted and the cascade protein expression pattern is altered in cone relative to rod BCs. Finally, the visual responses of RGCs are dramatically decreased in Lrit3-/- retina.<br /> <br /> Zeitz C., et al., Am J Hum Genet. 2013;92(1):67-75.<br /> Neuillé,M., et al., PLOS One. 2014;9(3):1-13.
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