Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina

Abstract

In many forms of retinal degeneration, photoreceptors die but inner retinal circuits remain intact. In the rd1 mouse, an established model for blinding retinal diseases, spontaneous activity in the coupled network of AII amacrine and ON cone bipolar cells leads to rhythmic bursting of ganglion cells. Since such activity could impair retinal and/or cortical responses to restored photoreceptor function, understanding its nature is important for developing treatments of retinal pathologies. Here we analyzed a compartmental model of the wild-type mouse AII amacrine cell to predict that the cell's intrinsic membrane properties, specifically, interacting fast Na and slow, M-type K conductances, would allow its membrane potential to oscillate when light-evoked excitatory synaptic inputs were withdrawn following photoreceptor degeneration. We tested and confirmed this hypothesis experimentally by recording from AIIs in a slice preparation of rd1 retina. Additionally, recordings from ganglion cells in a whole mount preparation of rd1 retina demonstrated that activity in AIIs was propagated unchanged to elicit bursts of action potentials in ganglion cells. We conclude that oscillations are not an emergent property of a degenerated retinal network. Rather, they arise largely from the intrinsic properties of a single retinal interneuron, the AII amacrine cell.

Aberrant activity in retinal degeneration impairs central visual processing and relies on Cx36-containing gap junctions

“…To test for this, we selectively blocked aberrant bursting activity in rd10 RGCs by including meclofenamic acid (MFA, 50 μM) into the bathing solution. This treatment has been shown to target gap junctions in AII amacrine cells, a pacemaker of the aberrant activity (Trenholm et al, 2012; Choi et al, 2014). Indeed, MFA had an effect of reducing the F i of spontaneous bursts in rd10 RGCs and significantly improved the discrimination of light-evoked activity (17.52 ± 4.36 to 93.93 ± 9.78 Hz, n = 15; p < 0.0001).…”

“…Aberrant activity in RD is primarily attributed to AII amacrine cell membrane oscillations, which are reliant on gap junction coupling (Trenholm et al, 2012; Choi et al, 2014). While the roles of AII amacrine cells and gap junctions in RD are becoming clear, it is unknown how mechanisms that regulate gap junctions lead to aberrant activity.…”

“…Several models have emerged that address this question. According to one, a reduction in synaptic light-dependent input in RD leads to hyperpolarization in AII amacrine cells, leading directly to intrinsic membrane oscillations that drive aberrant activity; in this model, electrical coupling is relevant only insofar as it affects AII hyperpolarization (Choi et al, 2014). In another model, oscillations arise from heterogeneities in the respective electrical properties of AII amacrine cells and ON cone bipolar cells, which interact via gap junctions to induce an oscillatory network (Trenholm et al, 2012).…”

“…In the retina, aberrant activity originates in AII amacrine cells and relies on excessive activation of gap junctions (Trenholm et al, 2012; Choi et al, 2014). Since AII amacrine cell gap junctions are comprised of Cx36 (Deans et al, 2002), we next hypothesized that genetic deletion of Cx36 would reduce aberrant hyperactivity in RD RGCs.…”

On the computation of a retina resistivity profile for applications in multi-scale modeling of electrical stimulation and absorption

“…The resolution ranges across a large spatial scale, from specific ionic current activity at the cellular membrane or a synapse (pm to µm), to large-scale models considering the current distribution across prosthetic electrode arrays and bulk tissue (µm to cm). For example, in the retina, single cell models based on measured morphologies and membrane properties have been used to analyze the passive and active properties of cell membranes (Usui et al 1996, Greenberg et al 1999), the dynamics of voltage-gated ion channels (Freeman et al 2011, Kameneva et al 2011), the stimulation region due to external electrodes (Schiefer and Grill 2006), and for modeling observed cell-type-specific phenomena (Fohlmeister et al 2010, Choi et al 2014). These models have quantified the cellular behavior, and have given insight as to what their roles may be in retinal circuitry.…”