Pharmacological Analysis of Intrinsic Neuronal Oscillations in rd10 Retina

Abstract

In the widely used mouse model of retinal degeneration, rd1, the loss of photoreceptors leads to rhythmic electrical activity of around 10–16 Hz in the remaining retinal network. Recent studies suggest that this oscillation is formed within the electrically coupled network of AII amacrine cells and ON-bipolar cells. A second mouse model, rd10, displays a delayed onset and slower progression of degeneration, making this mouse strain a better model for human retinitis pigmentosa. In rd10, oscillations occur at a frequency of 3–7 Hz, raising the question whether oscillations have the same origin in the two mouse models. As rd10 is increasingly being used as a model to develop experimental therapies, it is important to understand the mechanisms underlying the spontaneous rhythmic activity. To study the properties of oscillations in rd10 retina we combined multi electrode recordings with pharmacological manipulation of the retinal network. Oscillations were abolished by blockers for ionotropic glutamate receptors and gap junctions. Frequency and amplitude of oscillations were modulated strongly by blockers of inhibitory receptors and to a lesser extent by blockers of HCN channels. In summary, although we found certain differences in the pharmacological modulation of rhythmic activity in rd10 compared to rd1, the overall pattern looked similar. This suggests that the generation of rhythmic activity may underlie similar mechanisms in rd1 and rd10 retina.

Viability of Mouse Retinal Explant Cultures Assessed by Preservation of Functionality and Morphology

“…Organotypic retinal explant cultures have been used to study retinal development, [14][15][16] retinal diseases and injuries, [17][18][19][20][21][22][23][24][25][26] drug screening, 3,[27][28][29][30][31][32][33] and retinal stem cell therapies. 8,34,35 The culture systems also have high potential outside these fields, and they could be beneficial for completely new fields, including prion research and, specifically, prion organo-typic slice culture assays.…”

Electrical stimulation of the retina: aspects arising from retinal noise

“…Another aspect of this issue is consequences of the massive loss of photoreceptors and retinal remodeling in an animal with retinal degeneration contributing to emergence the pathological background activity of the RGCs with bursts of spikes at the rate of ~5 to ~10 Hz. [27][28][29][30][31][32][33][34][35] The prominent signs of the rd1 and rd10 retinas compared to the wild-type retina are the arising of spontaneous activity, which is characterized by rhythmic bursts of RGC spikes phase-locked with oscillations of local field potentials (LFPs). Aberrant rhythmic hyperactivity in RGCs has been detected in several strains of mice and rats with hereditary degenerations of the retina.…”

“…The prevailing theory explaining the arising of this pathological spontaneous rhythm in the photoreceptor-degenerated rd1 and rd10 mice retinas relates these oscillations to an intrinsic property of the electrically-coupled network of AII amacrine and ON cone bipolar cell. 29,30,33,34,[36][37][38] Prospects of the prosthetic stimulation of the retina are dependent on how accurate visual information will be represented in the electrically evoked activity of RGCs transmitted to the brain. Currently, it is not entirely clear how significantly the alterations of the circuitry of degenerating retina and the aberrant rhythmic hyperactivity can hamper the generation of electrically evoked activity.…”

“…105 Regular oscillatory discharges of the RGCs were demonstrated in several rodent strains with retinal degeneration. [27][28][29][30][31][32][33][34][35] The RGCs of the rd1 and rd10 mouse exhibit an aberrant periodic activity -rhythmic discharges with an average frequency of about 7-10 Hz. 30,106,107 Peaks of the spikes' activity correlated with the local field potentials (LPFs), which reflect the average synchronized excitatory input to the retinal ganglion cells.…”

Zukünftige Entwicklungen bei implantierbaren Netzhautprothesen

“…Neben den anatomischen Veränderungen kommt es aber auch zu funktionalen Veränderungen. In vielen Tiermodellen der RP lassen sich im Gegensatz zur normalen Netzhaut langsame Oszillationen von Feldpotenzialen messen, eine deutlich reduzierte Frequenz spontan auftretender Aktionspotenziale und die Kopplung von Salven solcher Aktionspotenziale an bestimmte Phasen der Oszillationen [10,11,12]. Die Ursache dieser atypischen Spontanaktivität ist nicht vollständig geklärt.…”