A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function

This article describes a mouse model of the human disease complete congenital stationary night blindness in which the mutation reduces but does not eliminate GRM6 expression and bipolar cell function, a phenotype distinct from that seen in other Grm6 mouse models.

Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation

Mutations in TRPM1 are found in humans with an autosomal recessive form of complete congenital stationary night blindness (cCSNB). The Trpm1−/− mouse has been an important animal model for this condition. Here we report a new mouse mutant, tvrm27, identified in a chemical mutagenesis screen. Genetic mapping of the no b-wave electroretinogram (ERG) phenotype of tvrm27 localized the mutation to a chromosomal region that included Trpm1. Complementation testing with Trpm1−/− mice confirmed a mutation in Trpm1. Sequencing identified a nucleotide change in exon 23, converting a highly conserved alanine within the pore domain to threonine (p.A1068T). Consistent with prior studies of Trpm1−/− mice, no anatomical changes were noted in the Trpm1 tvrm27/tvrm27 retina. The Trpm1 tvrm27/tvrm27 phenotype is distinguished from that of Trpm1−/− by the retention of TRPM1 expression on the dendritic tips of depolarizing bipolar cells (DBCs). While ERG b-wave amplitudes of Trpm1+/− heterozygotes are comparable to wild type, those of Trpm1+/ tvrm27 mice are reduced by 32%. A similar reduction in the response of Trpm1+/ tvrm27 DBCs to LY341495 or capsaicin is evident in whole cell recordings. These data indicate that the p.A1068T mutant TRPM1 acts as a dominant negative with respect to TRPM1 channel function. Furthermore, these data indicate that the number of functional TRPM1 channels at the DBC dendritic tips is a key factor in defining DBC response amplitude. The Trpm1 tvrm27/tvrm27 mutant will be useful for elucidating the role of TRPM1 in DBC signal transduction, for determining how Trpm1 mutations impact central visual processing, and for evaluating experimental therapies for cCSNB.

Pharmacological analysis of the rat cone electroretinogram

The electroretinogram (ERG) of the cone system provides a useful noninvasive measure of the activity of the cone pathway. Despite a wide application of the cone ERG in the study of rodent models of human hereditary retinal disease, the cellular origins of the rat cone ERG have not been well defined. Here, we address this issue using a pharmacological approach that has been used previously to derive ERG response components. Agents that impair synaptic transmission at well-defined retinal loci were dissolved in saline and injected into the vitreous of adult Sprague-Dawley rats anesthetized with ketamine/xylazine, and cone ERGs were recorded approximately 2 h later. Analysis of the resulting waveforms indicated that the rat cone ERG includes a relatively small-amplitude component of negative polarity that is derived from the activity of cone photoreceptors, and perhaps retinal glial (Müller) cells. The cone depolarizing bipolar cell pathway contributes a positive potential of large amplitude to the rat cone ERG. In comparison, the contribution of hyperpolarizing bipolar cells is of negative polarity and of much smaller amplitude. The inner retina contributes a negative wave upon which higher frequency oscillations are superimposed. These results provide a foundation for interpreting changes in the waveform of the rat cone ERG that may be observed following genetic alteration or other experimental treatment.