Abstract
Purpose :
Fat3, a member of the Fat family of atypical cadherins, is critical for the development of retinal circuitry. The deletion of Fat3 from the mouse retina impairs amacrine cell migration, neurite retraction, and the proper location of synapses, resulting in the formation of ectopic synaptic layers. However, it is unknown how retinal function is affected by these developmental cellular defects. To investigate this question, we examined retinal function of Fat3-deficienct mice.
Methods :
Mice were dark adapted overnight before being anesthetized for in vivo electroretinography (ERG) recordings. Four types of ERG recordings were performed: 1) scotopic test, 2) photopic test, 3) flicker test up to 50 Hz, and 4) three-second step light test. The photopic visual acuity of Fat3-/- mice was measured using the optomotor behavioral assay. In addition, to test if mice can perceive flickered light, a contextual and vision-cued fear conditioning (CVFC) test was designed and applied to Fat3-/- mice. Additional immunohistochemistry and in vivo ERG experiments were performed on Grik1-/- , Grm6-/-, and Grik1-/-Grm6-/- mice to look for effects due to perturbations in bipolar cells.
Results :
Fat3-/- eyes did not show a significant difference in the scotopic ERG, photopic ERG or photopic visual acuity compared to the controls. However, the flicker ERG tests revealed severely decreased amplitude and delayed implicit time from Fat3-/- eyes at the high temporal frequencies (i.e. >20 Hz) compared to the controls. Fat3-/- mice also presented impaired perception of 33 Hz flashes as measured by the CVFC test. Fat3-/- eyes showed diminished d-wave amplitude in the step ERG test, which correlated with decreased GRIK1 expression in OFF-bipolar cells (BC), in which Fat3 mRNA was enriched. Grik1-/- eyes presented a diminished d-wave, slightly decreased 30 Hz amplitude, and advanced 20 Hz implicit time.
Conclusions :
These results suggest that Fat3 is critical for OFF-BC function and for retinal processing of visual signals at high temporal frequency. Fat3 is not required for basic light sensation in dark or daylight conditions. Fat3 also appears not to be critical for normal spatial visual resolution in daylight conditions. Additional results from Grm6-/- and Grik1-/-Grm6-/- mice suggest that the function of ON-BCs, in addition to the function of OFF-BCs, might be compromised by Fat3-deficiency, contributing to the unique fast vision phenotype.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.