Network Deficiency Exacerbates Impairment in a Mouse Model of Retinal Degeneration

Abstract

Neural oscillations play an important role in normal brain activity, but also manifest during Parkinson’s disease, epilepsy, and other pathological conditions. The contribution of these aberrant oscillations to the function of the surviving brain remains unclear. In recording from retina in a mouse model of retinal degeneration (RD), we found that the incidence of oscillatory activity varied across different cell classes, evidence that some retinal networks are more affected by functional changes than others. This aberrant activity was driven by an independent inhibitory amacrine cell oscillator. By stimulating the surviving circuitry at different stages of the neurodegenerative process, we found that this dystrophic oscillator further compromises the function of the retina. These data reveal that retinal remodeling can exacerbate the visual deficit, and that aberrant synaptic activity could be targeted for RD treatment.

Functional changes in Tg P23H-1 rat retinal responses: differences between ON and OFF pathway transmission to the superior colliculus

“…These differences suggest a differential effect of photoreceptor degeneration on the ON and OFF retinal pathways. Published data in the rd1 mouse indicate that a large number of rhythmic NR RGCs have ON morphology (Yee et al 2012). This suggests that in the Tg P23H-1 retina, both pathways likely have rhythmic spontaneous activity as the retina degenerates.…”

Block of Gap Junctions Eliminates Aberrant Activity and Restores Light Responses during Retinal Degeneration

“…Shortly after disease onset, alterations to neuronal physiology occur, and oscillatory activity develops in bipolar, amacrine, and ganglion cells (Margolis et al, 2008;Borowska et al, 2011). This aberrant neuronal activity can exacerbate visual impairment, as it obscures signaling from bipolar cells to ganglion cells (Yee et al, 2012). Thus, the loss of photoreceptors is compounded by maladaptive interactions within the inner retinal network, as neuronal oscillations interfere with signal transmission from the retina to the brain.…”

“…A possible mechanism is the disruption of a network of gap junction-linked amacrine and bipolar cells, which has been shown to oscillate in wild-type (wt) retina when metabotropic glutamate receptors (mGluRs) are blocked, inducing conditions similar to the loss of photoreceptors (Trenholm et al, 2012). It has been found that blocking gap junction transmission significantly reduces aberrant oscillations (Borowska et al, 2011;Menzler and Zeck, 2011;Yee et al, 2012).…”

“…Visual impairment from RD occurs as a result of progressive photoreceptor degeneration, compounded by the concurrent structural remodeling of inner retinal neurons, which includes changes in glutamate receptor expression, and synaptic disorganization (for review, see Jones et al, 2012). Shortly after disease onset, alterations to neuronal physiology occur, and oscillatory activity develops in bipolar, amacrine, and ganglion cells (Margolis et al, 2008;Borowska et al, 2011). This aberrant neuronal activity can exacerbate visual impairment, as it obscures signaling from bipolar cells to ganglion cells (Yee et al, 2012).…”

Transient receptor potential cation channel, subfamilies V, member 1 (TRPV1) and M, member 1 (TRPM1) contribute to neural signaling in mouse retina.

“…In mice, genetically distinct GCs have been categorized morphologically and functionally (see Sanes and Masland, 2015 for a review). Approximately half of mice GCs have been classified in this way and evidence thus far shows a similar pattern to the cat and primate (Sagdullaev & McCall, 2005;van Wyk et al, 2009;Hong et al, 2011, Yee et al, 2012, Sanes and Masland, 2015.…”