Abstract
SUMMARYSpecificity 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.
Highlights
Circuit remodeling is a conserved strategy used to refine developing neural circuits across the nervous system
We focused our analysis on a specific type of retinal ganglion cells (RGCs), the alpha ON-sustained (AON-S) RGCs because they are conserved across some species (Peichl, 1991), easy to identify due to their large cell body and characteristic stratification, and, crucially, its connectivity pattern with presynaptic bipolar cells (BCs) is known from early postnatal ages to adulthood (Morgan et al, 2011; Schwartz et al, 2012)
We explored the possibility that during degeneration the connectivity pattern recapitulates the developmental program by labeling rod BCs (RBCs), mapping PSD95 apposed to their axon terminals (Figure 3A), and creating RBC-RGC connectivity maps (Figure 3B)
Summary
Circuit remodeling is a conserved strategy used to refine developing neural circuits across the nervous system. While developing circuits typically eliminate aberrant or extraneous synaptic connections during a critical period of refinement, miswired and/or functional connections can form between resilient or regenerating neurons after injury (Beier et al, 2017, 2018; Haverkamp et al, 2006; Shen et al, 2020; Yoshimatsu et al, 2016). We use a well-characterized circuit in the retina to investigate the extent to which presynaptic inputs remodel with degenerating postsynaptic neurons, quantifying the rewiring of presynaptic bipolar cells (BCs) and alterations of their synapses when their postsynaptic neurons, retinal ganglion cells (RGCs), are degenerating. Loss of photoreceptors leads to structural and synaptic plasticity and dendritic remodeling in second-order BCs (Care et al, 2019). Injury to the RGC is the hallmark of glaucoma, with synapse loss and dendritic shrinkage recognized as early events in RGC degeneration (Della Santina et al, 2013; Ou et al, 2016)
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