Genetic Dissection of Horizontal Cell Inhibitory Signaling in Mice in Complete Darkness in Vivo

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2015 May 30

PMID 26024096

Citations 8

Authors

Bruce A Berkowitz

Geoffrey G Murphy

Cheryl Mae Craft

D James Surmeier

Robin Roberts

Affiliations

Soon will be listed here.

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 L-type calcium channels (LTCCs) are open in complete darkness in the mouse retina in vivo.

Methods: Dark-adapted wild-type (wt), CACNA1F (Ca(v)1.4(-/-)), arrestin-1 (Arr1(-/-)), and CACNA1D (Ca(v)1.3(-/-)) C57Bl/6 mice 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 Ca(v)1.2 channels in vivo.

Results: Knockout mice predicted to have impaired HC inhibitory signaling (Ca(v)1.4(-/-) 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., Ca(v)1.2, 1.3, and 1.4) in rods and inner retina than that in DIL-treated Ca(v)1.4(-/-) mice (i.e., Ca(v)1.3). The Ca(v)1.3(-/-) + DIL-treated mice exhibited evidence for a compensatory contribution from Ca(v)1.2 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.

Citing Articles

Knockout of Ca1.3 L-type calcium channels in a mouse model of retinitis pigmentosa.

Kilicarslan I, Zanetti L, Novelli E, Schwarzer C, Strettoi E, Koschak A Sci Rep. 2021; 11(1):15146.

PMID: 34312410 PMC: 8313562. DOI: 10.1038/s41598-021-94304-3.

Preventing diabetic retinopathy by mitigating subretinal space oxidative stress .

Berkowitz B Vis Neurosci. 2020; 37:E002.

PMID: 32536351 PMC: 7310384. DOI: 10.1017/S0952523820000024.

Applications of Manganese-Enhanced Magnetic Resonance Imaging in Ophthalmology and Visual Neuroscience.

Deng W, Faiq M, Liu C, Adi V, Chan K Front Neural Circuits. 2019; 13:35.

PMID: 31156399 PMC: 6530364. DOI: 10.3389/fncir.2019.00035.

Manganese-Enhanced Magnetic Resonance Imaging: Overview and Central Nervous System Applications With a Focus on Neurodegeneration.

Cloyd R, Koren S, Abisambra J Front Aging Neurosci. 2019; 10:403.

PMID: 30618710 PMC: 6300587. DOI: 10.3389/fnagi.2018.00403.

D-cis-Diltiazem Can Produce Oxidative Stress in Healthy Depolarized Rods In Vivo.

Berkowitz B, Podolsky R, Farrell B, Lee H, Trepanier C, Berri A Invest Ophthalmol Vis Sci. 2018; 59(7):2999-3010.

PMID: 30025125 PMC: 5995482. DOI: 10.1167/iovs.18-23829.

References

Buchner D, Trudeau M, Meisler M . SCNM1, a putative RNA splicing factor that modifies disease severity in mice. Science. 2003; 301(5635):967-9. DOI: 10.1126/science.1086187. View

Paques M, Tadayoni R, Sercombe R, Laurent P, Genevois O, Gaudric A . Structural and hemodynamic analysis of the mouse retinal microcirculation. Invest Ophthalmol Vis Sci. 2003; 44(11):4960-7. DOI: 10.1167/iovs.02-0738. View

Baumann L, Gerstner A, Zong X, Biel M, Wahl-Schott C . Functional characterization of the L-type Ca2+ channel Cav1.4alpha1 from mouse retina. Invest Ophthalmol Vis Sci. 2004; 45(2):708-13. DOI: 10.1167/iovs.03-0937. View

McRory J, Hamid J, Doering C, Garcia E, Parker R, Hamming K . The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution. J Neurosci. 2004; 24(7):1707-18. PMC: 6730460. DOI: 10.1523/JNEUROSCI.4846-03.2004. View

Lipscombe D, Helton T, Xu W . L-type calcium channels: the low down. J Neurophysiol. 2004; 92(5):2633-41. DOI: 10.1152/jn.00486.2004. View

LaVail M, Sidman R . Differential effect of the rd mutation on rods and cones in the mouse retina. Invest Ophthalmol Vis Sci. 1978; 17(6):489-98. View

Glossmann H, Linn T, Rombusch M, Ferry D . Temperature-dependent regulation of d-cis-[3H]diltiazem binding to Ca2+ channels by 1,4-dihydropyridine channel agonists and antagonists. FEBS Lett. 1983; 160(1-2):226-32. DOI: 10.1016/0014-5793(83)80972-7. View

Drapeau P, Nachshen D . Manganese fluxes and manganese-dependent neurotransmitter release in presynaptic nerve endings isolated from rat brain. J Physiol. 1984; 348:493-510. PMC: 1199413. DOI: 10.1113/jphysiol.1984.sp015121. View

Yang X, Wu S . Feedforward lateral inhibition in retinal bipolar cells: input-output relation of the horizontal cell-depolarizing bipolar cell synapse. Proc Natl Acad Sci U S A. 1991; 88(8):3310-3. PMC: 51436. DOI: 10.1073/pnas.88.8.3310. View

10.

CARLSON R, Masco D, Brooker G, Spiegel S . Endogenous ganglioside GM1 modulates L-type calcium channel activity in N18 neuroblastoma cells. J Neurosci. 1994; 14(4):2272-81. PMC: 6577150. View

11.

Johansen O, Vaaler S, Jorde R, Reikeras O . Increased plasma glucose levels after Hypnorm anaesthesia, but not after Pentobarbital anaesthesia in rats. Lab Anim. 1994; 28(3):244-8. DOI: 10.1258/002367794780681723. View

12.

Schmitz Y, Witkovsky P . Dependence of photoreceptor glutamate release on a dihydropyridine-sensitive calcium channel. Neuroscience. 1997; 78(4):1209-16. DOI: 10.1016/s0306-4522(96)00678-1. View

13.

Crawley J, Belknap J, Collins A, Crabbe J, Frankel W, Henderson N . Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl). 1997; 132(2):107-24. DOI: 10.1007/s002130050327. View

14.

Strom T, Nyakatura G, Hellebrand H, Lorenz B, Weber B, Wutz K . An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet. 1998; 19(3):260-3. DOI: 10.1038/940. View

15.

Connor J, McCormack K, Pletsch A, Gaeta S, Ganetzky B, Chiu S . Genetic modifiers of the Kv beta2-null phenotype in mice. Genes Brain Behav. 2005; 4(2):77-88. DOI: 10.1111/j.1601-183X.2004.00094.x. View

16.

Hemara-Wahanui A, Berjukow S, Hope C, Dearden P, Wu S, Wilson-Wheeler J . A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc Natl Acad Sci U S A. 2005; 102(21):7553-8. PMC: 1140436. DOI: 10.1073/pnas.0501907102. View

17.

Mansergh F, Orton N, Vessey J, Lalonde M, Stell W, Tremblay F . Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Hum Mol Genet. 2005; 14(20):3035-46. DOI: 10.1093/hmg/ddi336. View

18.

Morgans C, Bayley P, Oesch N, Ren G, Akileswaran L, Taylor W . Photoreceptor calcium channels: insight from night blindness. Vis Neurosci. 2005; 22(5):561-8. DOI: 10.1017/S0952523805225038. View

19.

Douglas R, Alam N, Silver B, McGill T, Tschetter W, Prusky G . Independent visual threshold measurements in the two eyes of freely moving rats and mice using a virtual-reality optokinetic system. Vis Neurosci. 2005; 22(5):677-84. DOI: 10.1017/S0952523805225166. View

20.

Berkowitz B, Roberts R, Goebel D, Luan H . Noninvasive and simultaneous imaging of layer-specific retinal functional adaptation by manganese-enhanced MRI. Invest Ophthalmol Vis Sci. 2006; 47(6):2668-74. DOI: 10.1167/iovs.05-1588. View