Date on Master's Thesis/Doctoral Dissertation
12-2014
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Psychological and Brain Sciences
Committee Chair
McCall, Maureen Ann
Committee Co-Chair (if applicable)
Borghuis, Bart
Committee Member
DeMarco, Paul J.
Committee Member
Gregg, Ronald
Committee Member
Lyle, Keith
Subject
Night vision--Genetic aspects; Retina--Abnormalities
Abstract
Complete Congenital Stationary Night Blindness (cCSNB) is a rare hereditary retinal disorder characterized by abnormal night vision. cCSNB is caused by postsynaptic defects in On bipolar cells (BCs) and is identified by the presence of an electroretinogram (ERG) with a normal a-wave, corresponding to photoreceptor function, and the absence of a b-wave, corresponding to a failure of On BC function. Through the study of genetic mutations in mouse that result in no b-wave ERG phenotypes, several proteins have been identified that play crucial roles in On BC signal transmission. I focused on four mouse models of cCSNB; Nyxnob (Nyctalopin mutant), mGluR6-/- (mGluR6 knockout), Gpr179nob5 (GPR179 mutant), and Lrit3-/- (LRIT3 knockout). These mutations effect proteins expressed by On BCs (rod and On Cone BCs). While all models of cCSNB share a no b-wave ERG phenotype I have discovered that several models differ. The differences between cCSNB animal models provide important clues into the functional roles of the proteins effected by the mutations. Specifically, Nyxnob retinal ganglion cells (RGCs), the output neurons of the retina, exhibit robust 3-5 Hz rhythmic spiking while mGluR6-/- RGCs rarely do. I explored potential mechanisms which underlie this phenomenon, not only by examining RGC activity, but also the properties of the upstream rod BCs which provide excitatory input to RGCs. I found that differences in the resting state of Nyxnob and mGluR6-/- rod BCs correlate with the differences in RGC rhythmic spiking activity. Also, I discovered that nyctalopin is required for normal potassium conductance in rod BCs. Additionally, I examined the role of two recently identified proteins expressed in On BCs, GPR179 (Peachey et al., 2012; Ray et al., 2014) and LRIT3 (Zeitz et al., 2013; Neuille et al., 2014). I discovered that GPR179 sets the sensitivity of the TRPM1 channel and is critical for a normal light-evoked response in rod BCs. I also discovered that LRIT3 is critical for the modulation and expression of TRPM1 channels in rod BC dendritic tips. My data not only add to the literature on animal models of cCSNB, but to the understanding of retinal circuitry in the normal retina.
Recommended Citation
Fransen, Kathryn Marie Heath, "Retinal synaptic function in the absence of the on pathway." (2014). Electronic Theses and Dissertations. Paper 1709.
https://doi.org/10.18297/etd/1709
