Impaired Transmission from Photoreceptors to Bipolar Cells: Mouse Models
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In response to light, photoreceptors normally decrease the rate of glutamate release at their terminal. This change is detected by two classes of bipolar cells, which are distinguished by whether they depolarize (DBCs) or hyperpolarize (HBCs) in response to light. The electroretinogram (ERG) can be used to monitor this process as the ERG a-wave reflects photoreceptor activity while the b-wave is generated by bipolar cell responses. As a consequence, a selective reduction in the ERG b-wave is usually indicative of a defect in transmission between photoreceptors and bipolar cells. This situation is encountered in naturally occurring and genetically engineered mice, the study of which shed light on the development and maintenance of the photoreceptor-to-bipolar cell synaptic process. For example, null mutations in the genes encoding mGluR6 or Gα0 eliminate the b-wave and confirm the role of these proteins in DBC signal transduction. A similar ERG pattern is seen in the nob (no b-wave) mouse, which is caused by a defect in nyx, encoding nyctalopin. Although the precise function of nyctalopin is unknown, the localization of nyctalopin transcripts to the outer nuclear layer indicates that this protein may play a critical role in the DBC response. Despite the lack of DBC function, ribbon synapses form normally in nob mice. Presynaptically, glutamate release is controlled by L-type calcium channels located on the photoreceptor terminal. The b-wave is selectively reduced in CNSβ2-null mice, lacking the β2 subunit of the L-type calcium channel in the central nervous system. In addition, the normal distribution of the pore-forming α1F subunit is markedly disturbed, indicating that the β2 subunit is required to guide the formation of a functional channel. Such channels are likely to be required for ribbon synapse formation, as ribbon structures are rarely encountered in CNSβ2-null mice. As the nob and CNSβ2-null mice involve genes that underlie two forms of congenital stationary night blindness, study of these animal models will expand our understanding of these rare human disorders.