Genetic dissection of horizontal cell inhibitory signaling in mice in complete darkness in vivo

Bruce A. Berkowitz*, Geoffrey G. Murphy, Cheryl Mae Craft, D. James Surmeier, Robin Roberts

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Purpose. To test the hypothesis that horizontal cell (HC) inhibitory signaling controls the degree to which rod cell membranes are depolarized as measured by the extent to which Ltype calcium channels (LTCCs) are open in complete darkness in the mouse retina in vivo. Methods. Dark-adapted wild-type (wt), CACNA1F (Cav1.4-/-), arrestin-1 (Arr1-/-), and CACNA1D (Cav1.3-/-) C57Bl/6 mi ce were studied. Manganese-enhanced MRI (MEMRI) evaluated the extent that rod LTCCs are open as an index of loss of HC inhibitory signaling. Subgroups were pretreated with D-cis-diltiazem (DIL) at a dose that specifically antagonizes Cav1.2 channels in vivo. Results. Knockout mice predicted to have impaired HC inhibitory signaling (Cav1.4-/- or Arr1-/-) exhibited greater than normal rod manganese uptake; inner retinal uptake was also supernormal. Genetically knocking out a closely associated gene not expected to impact HC inhibitory signaling (CACNA1D) did not generate this phenotype. The Arr1-/- mice exhibited the largest rod uptake of manganese. Manganese-enhanced MRI of DIL-treated Arr1-/- mice suggested a greater number of operant LTCC subtypes (i.e., Cav1.2, 1.3, and 1.4) in rods and inner retina than that in DIL-treated Caυ1.4-/- mice (i.e., Cav1.3). The Caυ1.3-/- + DILtreated mice exhibited evidence for a compensatory contribution from Cav1.2 LTCCs. Conclusions. The data suggest that loss of HC inhibitory signaling is the proximate cause leading to maximally open LTCCs in rods, and possibly inner retinal cells, in mice in total darkness in vivo, regardless of compensatory changes in LTCC subtype manifested in the mutant mice.

Original languageEnglish (US)
Pages (from-to)3132-3139
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number5
DOIs
StatePublished - 2015

Keywords

  • Inhibitory signaling
  • L-type calcium chananels
  • Manganese-enhanced MRI

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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