Intrinsically photosensitive ganglion cells contribute to plasticity in retinal wave circuits

Abstract

Correlated spontaneous activity in the developing nervous system is robust to perturbations in the circuits that generate it, suggesting that mechanisms exist to ensure its maintenance. We examine this phenomenon in the developing retina, where blockade of cholinergic circuits that mediate retinal waves during the first postnatal week leads to the generation of "recovered" waves through a distinct, gap junction-mediated circuit. Unlike cholinergic waves, these recovered waves were modulated by dopaminergic and glutamatergic signaling, and required the presence of the gap junction protein connexin 36. Moreover, in contrast to cholinergic waves, recovered waves were stimulated by ambient light via activation of melanopsin-expressing intrinsically photosensitive retinal ganglion cells. The involvement of intrinsically photosensitive retinal ganglion cells in this reconfiguration of wavegenerating circuits offers an avenue of retinal circuit plasticity during development that was previously unknown.retinal development | dopamine | degenerate circuit T he computations performed by neural circuits are not determined by hard-wired anatomy but rather can be altered by experience or different neuromodulatory states (1-3). This plasticity is particularly important during development, when neural circuits show remarkable robustness against perturbations that disrupt the patterned, spontaneous activity required for normal development (4). For example, giant depolarizing potentials in the developing hippocampus are maintained against decreases in gamma-aminobutyric acid (GABAergic) transmission by increasing the strength of glutamatergic transmission (5). Similarly, spontaneous network activity in the developing spinal cord is maintained against alterations in GABAergic transmission by changes in both the intrinsic excitability of individual neurons and changes in synaptic strength of glutamatergic synapses (6). The developing retina also shows robustness against perturbations in circuits that generate spontaneous retinal waves (4). For example, disruption of normal cholinergic transmission during the first postnatal week leads to the generation of waves via a distinct gap junction coupled network (7-9). These observations indicate that degenerate circuit mechanisms exist in the developing retina to maintain spontaneous activity.Here we explore the hypothesis that intrinsically photosensitive retinal ganglion cells (ipRGCs) contribute to this wave circuit plasticity. ipRGCs are a recently discovered class of photoreceptors that express the photopigment melanopsin (10) and are light sensitive in mice from birth, unlike rod and cone photoreceptors, which become photosensitive after 2 postnatal weeks of development (11). Although ipRGCs are typically involved in non-image-forming functions, such as entrainment of circadian rhythms (12), they have been shown to support intraretinal signaling via gap junction coupling and by signaling to dopaminergic amacrine cells (DACs) (13-15). Indeed, light stimulation of ipRGCs can modulate ...

Visual Circuit Development Requires Patterned Activity Mediated by Retinal Acetylcholine Receptors

“…However, these projections normally don’t emerge until P6-P8 (Triplett et al, 2009), while the unusual SC activity is already present at P3 in β2 −/− mice. Dynamic reorganization on a network level may be a common phenomenon in the early neonatal brain (Stacy et al, 2005; Kirkby and Feller, 2013), and could facilitate large scale compensatory rewiring in response to disruptions in neural activity resulting from a variety of neurodevelopmental insults and disorders (Ebert and Greenberg, 2013). …”

“…It is notable that waves in the null part of the retina are nearly absent; whereas in β2 −/− mice waves are significantly reduced in frequency, but persist, albeit with quite abnormal spatiotemporal dynamics. This suggests that compensatory mechanisms keep track of activity across the entire (or large swaths) of) the retina, and maintain Gap junction mediated waves in β2 −/− mice (Stacy et al, 2005; Kirkby and Feller, 2013), but are silent in β2-nAChR ‘null’ regions of Retβ2-cKO mice.…”

Retinal ganglion cell maps in the brain: implications for visual processing

“…As a general group, ipRGCs have been shown to influence mood, possibly via their inputs to the amygdala or habenula [21,27], and they have also been hypothesized to drive photic-induced migraine headache via their inputs to the posterior thalamic nuclei [28]. ipRGCs also play various developmental roles, including neonatal bright light avoidance [29], assembly of retinal vasculature [30], and patterning of early retinal activity [31,32] which in turn can influence RGC axonal refinements within the brain [32]. It is also intriguing that in both mice and primates, ipRGCs project to the dorsal lateral geniculate nucleus — the structure responsible for relaying light information to the cortex for conscious processing of visual images [22 • ,33,34 • ].…”

Spontaneous Network Activity and Synaptic Development

“…Interestingly, acute pharmacological perturbations of stage II waves reactivate gap-junctional wave mechanisms, similar to what is observed in β2 −/− and ChAT −/− mice (Stacy and others 2005). This suggests that the respective connections are suppressed, possibly by neuromodulatory influences, rather than disassembled (Kirkby and Feller 2013; Stacy and others 2005), presumably to enhance the robustness spontaneous network activity.…”