Kinetics of Inhibitory Feedback from Horizontal Cells to Photoreceptors: Implications for an Ephaptic Mechanism.
Inhibitory feedback from horizontal cells (HCs) to cones generates center-surround receptive fields and color opponency in the retina. Mechanisms of HC feedback remain unsettled, but one hypothesis proposes that an ephaptic mechanism may alter the extracellular electrical field surrounding photoreceptor synaptic terminals, thereby altering Ca(2+) channel activity and photoreceptor output. An ephaptic voltage change produced by current flowing through open channels in the HC membrane should occur with no delay. To test for this mechanism, we measured kinetics of inhibitory feedback currents in Ambystoma tigrinum cones and rods evoked by hyperpolarizing steps applied to synaptically coupled HCs. Hyperpolarizing HCs stimulated inward feedback currents in cones that averaged 8-9 pA and exhibited a biexponential time course with time constants averaging 14-17 ms and 120-220 ms. Measurement of feedback-current kinetics was limited by three factors: (1) HC voltage-clamp speed, (2) cone voltage-clamp speed, and (3) kinetics of Ca(2+) channel activation or deactivation in the photoreceptor terminal. These factors totaled ∼4-5 ms in cones meaning that the true fast time constants for HC-to-cone feedback currents were 9-13 ms, slower than expected for ephaptic voltage changes. We also compared speed of feedback to feedforward glutamate release measured at the same cone/HC synapses and found a latency for feedback of 11-14 ms. Inhibitory feedback from HCs to rods was also significantly slower than either measurement kinetics or feedforward release. The finding that inhibitory feedback from HCs to photoreceptors involves a significant delay indicates that it is not due to previously proposed ephaptic mechanisms.



Lateral inhibitory feedback from horizontal cells (HCs) to photoreceptors creates center-surround receptive fields and color-opponent interactions. Although underlying mechanisms remain unsettled, a longstanding hypothesis proposes that feedback is due to ephaptic voltage changes that regulate photoreceptor synaptic output by altering Ca(2+) channel activity. Ephaptic processes should occur with no delay. We measured kinetics of inhibitory feedback currents evoked in photoreceptors with voltage steps applied to synaptically coupled HCs and found that feedback is too slow to be explained by ephaptic voltage changes generated by current flowing through continuously open channels in HC membranes. By eliminating the proposed ephaptic mechanism for HC feedback regulation of photoreceptor Ca(2+) channels, our data support earlier proposals that synaptic cleft pH changes are more likely responsible.
Truhlsen Eye Institute and Department of Ophthalmology & Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, and.
Ted J
0000-0002-8642-866X
TJ
Warren
Truhlsen Eye Institute and Department of Ophthalmology & Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198.
Matthew J
0000-0003-1615-4314
MJ
Van Hook
Department of Biology and Courant Institute of Mathematical Sciences, New York University, New York, New York 10003.
Daniel
0000-0002-0439-8349
D
Tranchina
Truhlsen Eye Institute and Department of Ophthalmology & Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, and wbthores@unmc.edu.
Wallace B
0000-0001-7104-042X
WB
Thoreson
D000557:Ambystoma; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D008297:Male; D009415:Nerve Net / Q000502:physiology; D009431:Neural Conduction / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D010786:Photoreceptor Cells / Q000502:physiology*; D051248:Retinal Horizontal Cells / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
L-type calcium current; ephapse; horizontal cell; lateral inhibition; photoreceptor; retina
Vision Res. 1985;25(6):767-74
2992160
Vision Res. 1971 Oct;11(10):1195-6
5156791
Biochim Biophys Acta. 1985 Nov 7;820(2):305-14
4052426
Vision Res. 1986;26(1):33-44
3012877
J Physiol. 2008 Jun 15;586(12):2889-902
18420706
PLoS Biol. 2011 Jul;9(7):e1001107
21811399
J Physiol. 1984 Sep;354:557-75
6090654
PLoS Biol. 2014 May 20;12(5):e1001864
24844296
J Gen Physiol. 1956 May 20;39(5):651-73
13319654
Science. 2001 May 11;292(5519):1178-80
11349152
J Neurosci. 2005 Apr 20;25(16):4108-17
15843613
Front Hum Neurosci. 2013 Sep 23;7:612
24068997
Prog Retin Eye Res. 2012 Sep;31(5):407-41
22580106
J Neurosci. 2014 Aug 27;34(35):11826-43
25164677
Pflugers Arch. 1985 Oct;405(3):294-6
2415920
Vis Neurosci. 2005 May-Jun;22(3):317-24
16079007
Vision Res. 1996 Dec;36(24):3943-53
9068848
J Neurophysiol. 2006 Mar;95(3):1992-5
16371457
J Physiol. 2016 Nov 15;594(22):6661-6677
27345444
Eur J Neurosci. 2006 Jun;23(11):2983-90
16819987
J Neurophysiol. 2010 Jan;103(1):419-23
19923246
Invest Ophthalmol Vis Sci. 2004 Feb;45(2):708-13
14744918
PLoS Biol. 2015 Dec 10;13(12):e1002322
26656622
Eur J Neurosci. 2006 Jun;23(12):3176-86
16820008
J Neurosci. 2005 May 4;25(18):4633-40
15872111
J Neurosci. 2008 May 28;28(22):5691-5
18509030
Nat Rev Neurosci. 2014 Apr;15(4):250-63
24619342
Synapse. 2016 Jan;70(1):1-14
26541100
Eur J Neurosci. 2008 May;27(10):2575-86
18547244
Prog Brain Res. 2001;131:145-59
11420937
J Physiol. 2001 Jul 15;534(Pt. 2):489-500
11454966
Biophys J. 2012 Dec 5;103(11):2287-94
23283227
J Physiol. 1988 Dec;407:329-48
3256619
Vis Neurosci. 1990 Dec;5(6):571-83
2085473
J Gen Physiol. 2003 Dec;122(6):657-71
14610018
Nat Neurosci. 2014 Feb;17 (2):289-95
24413696
J Comp Neurol. 2015 Oct 1;523(14):2062-81
25823610
Proc R Soc Lond B Biol Sci. 1980 Jan 17;206(1165):439-63
6102392
Neuroscience. 1985 Jan;14(1):111-31
2579350
Physiol Rep. 2015 Sep;3(9):null
26416977
Nat Neurosci. 2014 Feb;17(2):262-8
24441679
Proc Natl Acad Sci U S A. 1978 Dec;75(12):6310-3
32538
J Physiol. 1983 May;338:395-412
6308247
J Physiol. 1973 Oct;234(1):163-98
4766219
Ergeb Physiol. 1974;69(0):97-188
4151806
Vis Neurosci. 1995 Nov-Dec;12(6):1105-26
8962830
J Biol Chem. 2007 Jun 1;282(22):16016-35
17405877
J Neurosci. 2009 May 13;29(19):6358-66
19439613
J Gen Physiol. 1994 Sep;104(3):567-91
7807061
J Neurophysiol. 1991 May;65(5):1197-206
1651374
J Neurosci. 2003 Nov 12;23(32):10249-57
14614083
J Physiol. 1973 Oct;234(1):199-216
4766220
J Neurosci. 1989 Mar;9(3):815-27
2538583
J Vis Exp. 2013 Jun 01;(76):null
23770753
J Physiol. 2009 May 15;587(Pt 10):2353-64
19332495
Front Cell Neurosci. 2014 Feb 03;8:20
24550779
Curr Opin Neurobiol. 2015 Apr;31:95-103
25265066
Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2414-8
11527958
Mol Pharmacol. 2005 Feb;67(2):470-9
15509715
J Physiol. 2013 Jul 1;591(13):3309-24
23613534
J Physiol. 1973 Nov;235(1):207-23
4778138
J Physiol. 2009 Feb 15;587(Pt 4):829-49
19124538
Proc R Soc Lond B Biol Sci. 1978 May 16;201(1144):309-15
27806
J Neurosci. 2006 Mar 1;26(9):2555-63
16510733
J Physiol. 2005 Dec 15;569(Pt 3):773-88
16223761
Philos Trans R Soc Lond B Biol Sci. 1973;265(872):471-89
4147132
eNeuro. 2016 Mar 10;3(2):null
27022629
Hum Mol Genet. 2005 Oct 15;14(20):3035-46
16155113