Publication in detail

Invest Ophthalmol Vis Sci 2009 Feb;50(2):505-15. Epub 2008 Oct

Effects of presynaptic mutations on a postsynaptic Cacna1s calcium channel co-localized with mGluR6 at mouse photoreceptor ribbon synapses.

Brandstaetter, JH; Dearden, P; Koentgen, F; Maw, MA; Specht, D; Tom, Dieck S.; Turner, P; Wolfrum, U; Wu, SB

Department of Biology, Animal Physiology, University of Erlangen-Nuremberg, Erlangen, Germany.

PURPOSE: Photoreceptor ribbon synapses translate light-dependent changes of membrane potential into graded transmitter release via L-type voltage-dependent calcium channel (VDCC) activity. Functional abnormalities (e.g., a reduced electroretinogram b-wave), arising from mutations of presynaptic proteins, such as Bassoon and the VDCCalpha1 subunit Cacna1f, have been shown to altered transmitter release. L-type VDCCalpha1 subtype expression in wild-type and mutant mice was examined, to investigate the underlying pathologic mechanism. METHODS: Two antisera against Cacna1f, and a Cacna1f mouse mutant (Cacna1fDeltaEx14-17) were generated. Immunocytochemistry for L-type VDCCalpha1 subunits and additional synaptic marker proteins was performed in wild-type, BassoonDeltaEx4-5 and Cacna1fDeltaEx14-17 mice. RESULTS: Active zone staining at photoreceptor ribbon synapses with a panalpha1 antibody colocalized with staining for Cacna1f in wild-type mouse retina. Similarly, in the BassoonDeltaEx4-5 mouse, residual mislocalized staining for panalpha1 and Cacna1f showed colocalization. Unlike the presynaptic location of Cacna1f and panalpha1 antibody staining, the skeletal muscle VDCCalpha1 subunit Cacna1s was present postsynaptically at ON-bipolar cell dendrites, where it colocalized with metabotropic glutamate receptor 6 (mGluR6). Surprisingly, Cacna1s labeling was severely downregulated in the BassoonDeltaEx4-5 and Cacna1fDeltaEx14-17 mutants. Subsequent analyses revealed severely reduced ON-bipolar cell dendritic expression of the sarcoplasmic reticulum Ca(2+) ATPase Serca2 in both mouse mutants and of mGluR6 in the Cacna1fDeltaEx14-17 mutant. CONCLUSIONS: Presynaptic mutations leading to reduced photoreceptor-to-bipolar cell signaling are associated with disturbances in protein expression within postsynaptic dendrites. Moreover, detection of Cacna1s and Serca2 in ON-bipolar cell dendrites in wild-type animals suggests a putative role in regulation of postsynaptic Ca(2+) flux.

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