DSCAM-mediated control of dendritic and axonal arbor outgrowth enforces tiling and inhibits synaptic plasticity

Abstract

Mature mammalian neurons have a limited ability to extend neurites and make new synaptic connections, but the mechanisms that inhibit such plasticity remain poorly understood. Here, we report that OFF-type retinal bipolar cells in mice are an exception to this rule, as they form new anatomical connections within their tiled dendritic fields well after retinal maturity. The Down syndrome cell-adhesion molecule () confines these anatomical rearrangements within the normal tiled fields, as conditional deletion of the gene permits extension of dendrite and axon arbors beyond these borders. deletion in the mature retina results in expanded dendritic fields and increased cone photoreceptor contacts, demonstrating that DSCAM actively inhibits circuit-level plasticity. Electrophysiological recordings from OFF bipolar cells showed enlarged visual receptive fields, demonstrating that expanded dendritic territories comprise functional synapses. Our results identify cell-adhesion molecule-mediated inhibition as a regulator of circuit-level neuronal plasticity in the adult retina.

Increased density and age‐related sharing of synapses at the cone to OFF bipolar cell synapse in the mouse retina

“…We hypothesized that an increase in the number of ON cone BCs could cause structural changes to the cone synapse. To test this, we asked if an increase in the number of ON BCs correlated with an increase in the size of the cone terminal, and provide one potential model to explain differences in the frequency at which BC4s cocontacted cones (Lee et al, ; Simmons et al, ; Wassle et al, ). We observed a significant increase in the number of both rod and non‐rod ON BCs in the Bax null retina compared to wt (Figure a–h).…”

“…Studies of neurite exploration and synaptic refinement in the inner retina have been challenging, due to the extreme density of synaptic contacts compared with other parts of the nervous system. Alternating stages of exploration and refinement have also been reported in the outer retina (D'Orazi, Suzuki, & Wong, 2014;Hoon et al, 2015;Huckfeldt et al, 2009;Simmons et al, 2017). Here, we leveraged the large synaptic terminal of cone photoreceptors in combination with genetic identification of a neuronal subpopulation to study the process of dendrite outgrowth and refinement in the outer retina (Boycott & Hopkins, 1991;Haverkamp, Grunert, & Wassle, 2000).…”

Dendrite morphogenesis from birth to adulthood

“…This structure serves as the anatomical basis for their spatial receptive fields, so one might assume that it would be static in the mature retina. Surprisingly, however, mouse rod bipolar cells expand their territories, increasing photoreceptor contacts, until about one month of age [32]; cone bipolars continue to expand until 3 months [33], well into mouse adulthood.…”

“…The phenotype arises in development but worsens into adulthood: Mutant bipolar dendrites continue expanding, exploring their environment, and establishing new cone synapses. Tiling errors can even be induced by adult Dscam gene ablation [33]. Therefore, one role of DSCAM is to suppress young adult dendritic plasticity mechanisms in mouse middle age.…”

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

“…Drosophila Dscam1 is essential for key aspects of neuronal wiring including axonal growth, guidance, targeting, and branching (Schmucker et al, 2000;Hummel et al, 2003;Chen et al, 2006;He et al, 2014;Dascenco et al, 2015), dendritic field organization (Hughes et al, 2007;Matthews et al, 2007;Soba et al, 2007), and synaptic connectivity (Millard et al, 2010). Homophilic self-recognition of DSCAMs is required in flies and mice for neurite repulsion and selfavoidance of sister-neurites in vivo (Hughes et al, 2007;Fuerst et al, 2008Fuerst et al, , 2010Hattori et al, 2008;Yamagata & Sanes, 2008;Simmons et al, 2017). Homophilic self-recognition of DSCAMs is required in flies and mice for neurite repulsion and selfavoidance of sister-neurites in vivo (Hughes et al, 2007;Fuerst et al, 2008Fuerst et al, , 2010Hattori et al, 2008;Yamagata & Sanes, 2008;Simmons et al, 2017).…”