Structural changes underlying neurodegenerative diseases include dismantling of synapses, degradation of circuitry, and even massive rewiring. Our limited understanding of synapse dismantling stems from the inability to control the timing and extent of cell death. In this study, selective ablation of cone photoreceptors in live mouse retina and tracking of postsynaptic partners at the cone-to-ON cone bipolar cell synapse reveals that early reaction to cone loss involves rapid and local changes in postsynaptic glutamate receptor distribution. Glutamate receptors disappear with a time constant of 2 h. Furthermore, binding of glutamate receptors by agonists and antagonists is insufficient to rescue glutamate receptor loss, suggesting that receptor allocation depends on the physical presence of cones. These findings demonstrate that the initial step in synapse disassembly involves postsynaptic receptor loss rather than dendritic retraction, providing insight into the early stages of neurodegenerative disease.

Sensory circuits use common strategies, such as convergence and divergence, typically at different synapses, to pool or distribute inputs. Inputs from different presynaptic cell types converge onto a common postsynaptic cell, acting together to shape neuronal output (Klausberger and Somogyi, 2008). Also, individual presynaptic cells contact several postsynaptic cell types, generating divergence of signals. Attaining such complex wiring patterns relies on the orchestration of many events across development, including axonal and dendritic growth and synapse formation and elimination (reviewed by Waites et al., 2005; Sanes and Yamagata, 2009). Recent work has focused on how distinct presynaptic cell types form stereotypic connections with an individual postsynaptic cell (Morgan et al., 2011; Williams et al., 2011), but how a single presynaptic cell type diverges to form distinct wiring patterns with multiple postsynaptic cell types during development remains unexplored. Here we take advantage of the compactness of the visual system's first synapse to observe development of such a circuit in mouse retina. By imaging three types of postsynaptic bipolar cells and their common photoreceptor targets across development, we found that distinct bipolar cell types engage in disparate dendritic growth behaviors, exhibit targeted or exploratory approaches to contact photoreceptors, and adhere differently to the synaptotropic model of establishing synaptic territories. Furthermore each type establishes its final connectivity patterns with the same afferents on separate time scales. We propose that such differences in strategy and timeline could facilitate the division of common inputs among multiple postsynaptic cell types to create parallel circuits with diverse function.

Our sense of sight relies on photoreceptors, which transduce photons into the nervous system's electrochemical interpretation of the visual world. These precious photoreceptors can be disrupted by disease, injury, and aging. Once photoreceptors start to die, but before blindness occurs, the remaining retinal circuitry can withstand, mask, or exacerbate the photoreceptor deficit and potentially be receptive to newfound therapies for vision restoration. To maximize the retina's receptivity to therapy, one must understand the conditions that influence the state of the remaining retina. In this review, we provide an overview of the retina's structure and function in health and disease. We analyze a collection of observations on photoreceptor disruption and generate a predictive model to identify parameters that influence the retina's response. Finally, we speculate on whether the retina, with its remarkable capacity to function over light levels spanning nine orders of magnitude, uses these same adaptational mechanisms to withstand and perhaps mask photoreceptor loss.

Loss of primary neuronal inputs inevitably strikes every neural circuit. The deafferented circuit could propagate, amplify, or mitigate input loss, thus affecting the circuit's output. How the deafferented circuit contributes to the effect on the output is poorly understood because of lack of control over loss of and access to circuit elements. Here, we control the timing and degree of rod photoreceptor ablation in mature mouse retina and uncover compensation. Following loss of half of the rods, rod bipolar cells mitigate the loss by preserving voltage output. Such mitigation allows partial recovery of ganglion cell responses. We conclude that rod death is compensated for in the circuit because ganglion cell responses to stimulation of half of the rods in an unperturbed circuit are weaker than responses after death of half of the rods. The dominant mechanism of such compensation includes homeostatic regulation of inhibition to balance the loss of excitation.

Neural circuits function in the face of changing inputs, either caused by normal variation in stimuli or by cell death. To maintain their ability to perform essential computations with partial inputs, neural circuits make modifications. Here, we study the retinal circuit's responses to changes in light stimuli or in photoreceptor inputs by inducing partial cone death in the mature mouse retina. Can the retina withstand or recover from input loss? We find that the excitatory pathways exhibit functional loss commensurate with cone death and with some aspects predicted by partial light stimulation. However, inhibitory pathways recover functionally from lost input by increasing spatiotemporal integration in a way that is not recapitulated by partially stimulating the control retina. Anatomically, inhibitory synapses are upregulated on secondary bipolar cells and output ganglion cells. These findings demonstrate the greater capacity for inhibition, compared with excitation, to modify spatiotemporal processing with fewer cone inputs.

Understanding a sensory system implies the ability to predict responses to a variety of inputs from a common model. In the retina, this includes predicting how the integration of signals across visual space shapes the outputs of retinal ganglion cells. Exi

Specific connectivity patterns among neurons create the basic architecture underlying parallel processing in our nervous system. Here we focus on the visual system's first synapse to examine the structural and functional consequences of sensory deprivation on the establishment of parallel circuits. Dark rearing reduces synaptic strength between cones and cone bipolar cells, a previously unappreciated effect of sensory deprivation. In contrast, rod bipolar cells, which utilize the same glutamate receptor to contact rods, are unaffected by dark rearing. Underlying the physiological changes, we find the localization of metabotropic glutamate receptors within cone bipolar, but not rod bipolar, cell dendrites is a light-dependent process. Furthermore, although cone bipolar cells share common cone partners, each bipolar cell type that we examined depends differentially on sensory input to achieve mature connectivity. Thus, visual experience differentially affects maturation of rod versus cone pathways and of cell types within the cone pathway.

Specificity and timing of synapse disassembly in the CNS are essential to learning how individual circuits react to neurodegeneration of the postsynaptic neuron. In sensory systems such as the mammalian retina, synaptic connections of second-order neurons are known to remodel and reconnect in the face of sensory cell loss. Here we analyzed whether degenerating third-order neurons can remodel their local presynaptic connectivity. We injured adult retinal ganglion cells by transiently elevating intraocular pressure. We show that loss of presynaptic structures occurs before postsynaptic density proteins and accounts for impaired transmission from presynaptic neurons, despite no evidence of presynaptic cell loss, axon terminal shrinkage, or reduced functional input. Loss of synapses is biased among converging presynaptic neuron types, with preferential loss of the major excitatory cone-driven partner and increased connectivity with rod-driven presynaptic partners, demonstrating that this adult neural circuit is capable of structural plasticity while undergoing neurodegeneration.