Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter, glutamate, from cone and rod photoreceptor terminals, and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition. There are two classes of bipolar cells, hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor, mGluR6, that signals to TRPM1, depolarizing in response to a light flash. Defects in transmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6, NYX, TRPM1, GPR179 and LRIT3 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largely unknown. The long term goal of this project is study the molecular interactions between LRIT3 and known and known components DBC signal transduction components.
The specific aims are: 1) determine the function of LRIT3 domains on rod and cone DBC mGluR6 signalplex assembly and signaling, and 2) Define protein interactions required for DBC assembly and synaptic function, and 3) determine the function of LRFN1 and 2 on cone synapse function. At the completion of this project, we will have characterized the function of LRIT3 and how it interacts with currently unknown presynaptic partners. Further, we will have identified new candidate genes for congenital stationary night blindness.
Vision requires a light signal be converted to an electrical signal, which is then transmitted to the brain via a neuronal network. The diseases being studied are referred to as congenital stationary night blindness. The studies in this proposal will characterize the nature of the defects and determine the function of newly identified proteins critical for normal vision, which will set the stage of therapeutic approaches in the future.
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