Rhythmic Ganglion Cell Activity in Bleached and Blind Adult Mouse Retinas

In retinitis pigmentosa – a degenerative disease which often leads to incurable blindness- the loss of photoreceptors deprives the retina from a continuous excitatory input, the so-called dark current. In rodent models of this disease this deprivation leads to oscillatory electrical activity in the remaining circuitry, which is reflected in the rhythmic spiking of retinal ganglion cells (RGCs). It remained unclear, however, if the rhythmic RGC activity is attributed to circuit alterations occurring during photoreceptor degeneration or if rhythmic activity is an intrinsic property of healthy retinal circuitry which is masked by the photoreceptor’s dark current. Here we tested these hypotheses by inducing and analysing oscillatory activity in adult healthy (C57/Bl6) and blind mouse retinas (rd10 and rd1). Rhythmic RGC activity in healthy retinas was detected upon partial photoreceptor bleaching using an extracellular high-density multi-transistor-array. The mean fundamental spiking frequency in bleached retinas was 4.3 Hz; close to the RGC rhythm detected in blind rd10 mouse retinas (6.5 Hz). Crosscorrelation analysis of neighbouring wild-type and rd10 RGCs (separation distance <200 µm) reveals synchrony among homologous RGC types and a constant phase shift (∼70 msec) among heterologous cell types (ON versus OFF). The rhythmic RGC spiking in these retinas is driven by a network of presynaptic neurons. The inhibition of glutamatergic ganglion cell input or the inhibition of gap junctional coupling abolished the rhythmic pattern. In rd10 and rd1 retinas the presynaptic network leads to local field potentials, whereas in bleached retinas additional pharmacological disinhibition is required to achieve detectable field potentials. Our results demonstrate that photoreceptor bleaching unmasks oscillatory activity in healthy retinas which shares many features with the functional phenotype detected in rd10 retinas. The quantitative physiological differences advance the understanding of the degeneration process and may guide future rescue strategies.

[1]  M. Avoli,et al.  GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity , 2011, Progress in Neurobiology.

[2]  K. Yau,et al.  Rod Sensitivity of Neonatal Mouse and Rat , 2005, The Journal of general physiology.

[3]  E J Chichilnisky,et al.  Behavioral / Systems / Cognitive Identification and Characterization of a Y-Like Primate Retinal Ganglion Cell Type , 2007 .

[4]  Rachel O.L. Wong,et al.  Failure to Maintain Eye-Specific Segregation in nob, a Mutant with Abnormally Patterned Retinal Activity , 2006, Neuron.

[5]  Mark S. Cembrowski,et al.  Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina. , 2014, Journal of neurophysiology.

[6]  S. Han,et al.  Spontaneous Oscillatory Rhythm in Retinal Activities of Two Retinal Degeneration (rd1 and rd10) Mice , 2011, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[7]  R. Masland,et al.  Spike train signatures of retinal ganglion cell types , 2007, The European journal of neuroscience.

[8]  Michael W. Reimann,et al.  A Biophysically Detailed Model of Neocortical Local Field Potentials Predicts the Critical Role of Active Membrane Currents , 2013, Neuron.

[9]  M. T. Davisson,et al.  Retinal degeneration mutants in the mouse , 2002, Vision Research.

[10]  M. Feller,et al.  Mechanisms underlying spontaneous patterned activity in developing neural circuits , 2010, Nature Reviews Neuroscience.

[11]  Dao-Qi Zhang,et al.  Functional integrity and modification of retinal dopaminergic neurons in the rd1 mutant mouse: roles of melanopsin and GABA. , 2013, Journal of neurophysiology.

[12]  Thomas Euler,et al.  Functional Stability of Retinal Ganglion Cells after Degeneration-Induced Changes in Synaptic Input , 2008, The Journal of Neuroscience.

[13]  Iman H. Brivanlou,et al.  Mechanisms of Concerted Firing among Retinal Ganglion Cells , 1998, Neuron.

[14]  G. Awatramani,et al.  Intrinsic oscillatory activity arising within the electrically coupled AII amacrine–ON cone bipolar cell network is driven by voltage‐gated Na+ channels , 2012, The Journal of physiology.

[15]  Xiaofeng Ma,et al.  Spontaneous Activity Promotes Synapse Formation in a Cell-Type-Dependent Manner in the Developing Retina , 2012, The Journal of Neuroscience.

[16]  Michael P. Andrews,et al.  Developmental time course distinguishes changes in spontaneous and light-evoked retinal ganglion cell activity in rd1 and rd10 mice. , 2011, Journal of neurophysiology.

[17]  Abduqodir H. Toychiev,et al.  Correlated Spontaneous Activity Persists in Adult Retina and Is Suppressed by Inhibitory Inputs , 2013, PloS one.

[18]  Karl Deisseroth,et al.  Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa , 2010, Science.

[19]  P. Detwiler,et al.  Network Oscillations Drive Correlated Spiking of ON and OFF Ganglion Cells in the rd1 Mouse Model of Retinal Degeneration , 2014, PloS one.

[20]  B. Sagdullaev,et al.  Network Deficiency Exacerbates Impairment in a Mouse Model of Retinal Degeneration , 2012, Front. Syst. Neurosci..

[21]  A. Lambacher,et al.  Identifying firing mammalian neurons in networks with high-resolution multi-transistor array (MTA) , 2011 .

[22]  Günther Zeck,et al.  Network Oscillations in Rod-Degenerated Mouse Retinas , 2011, The Journal of Neuroscience.

[23]  Woodrow L. Shew,et al.  Maximal Variability of Phase Synchrony in Cortical Networks with Neuronal Avalanches , 2012, The Journal of Neuroscience.

[24]  S. Stasheff,et al.  Emergence of sustained spontaneous hyperactivity and temporary preservation of OFF responses in ganglion cells of the retinal degeneration (rd1) mouse. , 2008, Journal of neurophysiology.

[25]  Douglas S Kim,et al.  Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration , 2008, Nature Neuroscience.

[26]  J. Lisman,et al.  Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis. , 1993, Experimental eye research.

[27]  Gautam B Awatramani,et al.  An Intrinsic Neural Oscillator in the Degenerating Mouse Retina , 2011, The Journal of Neuroscience.

[28]  Alfred Stett,et al.  Subretinal electronic chips allow blind patients to read letters and combine them to words , 2010, Proceedings of the Royal Society B: Biological Sciences.

[29]  Morven A. Cameron,et al.  Electrical Stimulation of Inner Retinal Neurons in Wild-Type and Retinally Degenerate (rd/rd) Mice , 2013, PloS one.

[30]  Armin Lambacher,et al.  Axonal Transmission in the Retina Introduces a Small Dispersion of Relative Timing in the Ganglion Cell Population Response , 2011, PloS one.

[31]  R. Masland,et al.  Physiological clustering of visual channels in the mouse retina. , 2011, Journal of neurophysiology.

[32]  Y. Goo,et al.  The slow wave component of retinal activity in rd/rd mice recorded with a multi-electrode array , 2007, Physiological measurement.

[33]  A. Feigenspan,et al.  Spontaneous Activity of Solitary Dopaminergic Cells of the Retina , 1998, The Journal of Neuroscience.

[34]  B. Rudy,et al.  Spontaneous oscillatory activity of starburst amacrine cells in the mouse retina. , 2005, Journal of neurophysiology.