Acid-sensing ion channel 3 in retinal function and survival.

PURPOSE: Changes in extracellular pH occur in the retina and directly affect retinal activity and phototransduction. The authors analyzed the expression in rodent retina of ASIC3, a sensor of extracellular acidosis, and used ASIC3 knockout mice to explore its role in retinal function and survival. METHODS: The expression and the role of ASIC3 were examined by immunolocalization and by comparing retinas from wild-type and knockout mice at different ages through electroretinography, retinal histology (light and electron microscopy), expression of glial fibrillary acidic protein (GFAP), analysis of cell apoptosis (TUNEL assay), and patch-clamp recordings in primary cultures of retinal ganglion cells (RGCs). RESULTS: ASIC3 is present in the rod inner segment of photoreceptors and in horizontal and some amacrine cells. ASIC3 is also detected in RGCs but does not significantly contribute to ASIC currents recorded in cultured RGCs. At 2 to 3 months, knockout mice experience a 19% enhancement of scotopic electroretinogram a-wave amplitude and a concomitant increase of b-wave amplitude without alteration of retinal structure. Older (8-month-old) knockout mice have 69% and 64% reductions in scotopic a- and b-waves, respectively, and reductions in oscillatory potential amplitudes associated with complete disorganization of the retina and degenerating rod inner segments. GFAP and TUNEL staining performed at 8 and 12 months of age revealed an upregulation of GFAP expression in Müller cells and the presence of apoptotic cells in the inner and outer retina. CONCLUSIONS: Inactivation of ASIC3 enhances visual transduction at 2 to 3 months but induces late-onset rod photoreceptor death, suggesting an important role for ASIC3 in maintaining retinal integrity.

Silencing acid-sensing ion channel 1a alters cone-mediated retinal function.

The action of extracellular protons on retinal activity and phototransduction occurs through pH-sensitive elements, mainly membrane conductances present on the different cell types of the outer and inner nuclear layers and of the ganglion cell layer. Acid-sensing ion channels (ASICs) are depolarizing conductances that are directly activated by protons. We investigated the participation of ASIC1a, a particular isoform of ASICs, in retinal physiology in vivo using electroretinogram measurements. In situ hybridization and immunohistochemistry localized ASIC1a in the outer and inner nuclear layers (cone photoreceptors, horizontal cells, some amacrine and bipolar cells) and in the ganglion cell layer. Both the in vivo knockdown of ASIC1a by antisense oligonucleotides and the in vivo blocking of its activity by PcTx1, a specific venom peptide, were able to decrease significantly and reversibly the photopic a- and b-waves and oscillatory potentials. Our study indicates that ASIC1a is an important channel in normal retinal activity. Being present in the inner segments of cones and inner nuclear layer cells, and mainly at synaptic cleft levels, it could participate in gain adaptation to ambient light of the cone pathway, facilitating cone hyperpolarization in brightness and modulating synaptic transmission of the light-induced visual signal.