Recently the gene causing incomplete congenital stationary night blindness (CSNB2) was identified and found to encode a retina-specific, voltage-activated calcium channel, alpha-1F. The disease is characterized by severely reduced nighttime (or rod-mediated) vision as well as abnormalities in daytime (or cone-mediated) vision. The electrophysiological and psychophysical phenotype of CSNB2 can be explained by a defect in synaptic transmission within the retina. We have found that the alpha-1F calcium channel is localized to rod photoreceptor and rod bipolar cell synaptic terminals in the rat and mouse retinas consistent with the night-blindness associated with CSNB2. Voltage-activated calcium channels are essential to the first two stages of visual processing in the retina, which occur at photoreceptor and bipolar cell ribbon synapses. At the ribbon synapse, calcium channels couple the graded electrical responses of the photoreceptor or bipolar cell to calcium-dependent, graded release of the excitatory neurotransmitter, glutamate. Our data suggest that the symptoms of CSNB2 are caused by a block of glutamate release at photoreceptor and bipolar cell ribbon synapses. A detailed characterization of the alpha -1F calcium channel is essential to understanding both the complex phenotype of CSNB2 and normal synaptic transmission in the retina. Yet the biophysical properties of alpha-1F calcium channels are not known. Nor is it known whether alpha-1F is present in cone photoreceptor and cone bipolar cell terminals, or whether other calcium channels mediate glutamate release in the cone pathway. The proposed experiments will address these questions.
The Specific Aims are to 1. Determine in detail the distribution and functional properties of the alpha-1F calcium channel subunit. 2. Identify retinal proteins that interact with alpha-1F. 3. Identify other voltage-activated calcium channels at retinal ribbon synapses. We will use a multidisciplinary approach involving molecular, biochemical, immunohistochemical and electrophysiological techniques to achieve these aims. The results of these experiments will provide insight into the composition and functional organization of retinal ribbon synapses and into the perturbation of retinal function associated with CSNB2.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014700-02
Application #
6830141
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Mariani, Andrew P
Project Start
2003-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
2
Fiscal Year
2005
Total Cost
$264,250
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Babai, N; Morgans, C W; Thoreson, W B (2010) Calcium-induced calcium release contributes to synaptic release from mouse rod photoreceptors. Neuroscience 165:1447-56
Jeffrey, Brett G; Morgans, Catherine W; Puthussery, Theresa et al. (2010) R9AP stabilizes RGS11-G beta5 and accelerates the early light response of ON-bipolar cells. Vis Neurosci 27:9-17
Zhang, Jianmei; Jeffrey, Brett G; Morgans, Catherine W et al. (2010) RGS7 and -11 complexes accelerate the ON-bipolar cell light response. Invest Ophthalmol Vis Sci 51:1121-9
Morgans, Catherine W; Kensel-Hammes, Patricia; Hurley, James B et al. (2009) Loss of the Synaptic Vesicle Protein SV2B results in reduced neurotransmission and altered synaptic vesicle protein expression in the retina. PLoS One 4:e5230
Morgans, Catherine W; Zhang, Jianmei; Jeffrey, Brett G et al. (2009) TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells. Proc Natl Acad Sci U S A 106:19174-8
Bayley, Philippa R; Morgans, Catherine W (2007) Rod bipolar cells and horizontal cells form displaced synaptic contacts with rods in the outer nuclear layer of the nob2 retina. J Comp Neurol 500:286-98
Quraishi, Salma; Gayet, Jacqueline; Morgans, Catherine W et al. (2007) Distribution of group-III metabotropic glutamate receptors in the retina. J Comp Neurol 501:931-43
Chang, Bo; Heckenlively, John R; Bayley, Philippa R et al. (2006) The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11-24
Morgans, Catherine W; Bayley, Philippa R; Oesch, Nicholas W et al. (2005) Photoreceptor calcium channels: insight from night blindness. Vis Neurosci 22:561-8