Bergmann Glia and the Recognition Molecule CHL1 Organize GABAergic Axons and Direct Innervation of Purkinje Cell Dendrites

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Abstract
The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG) fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1) is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation. Large principal neurons in vertebrate neural circuits often consist of distinct anatomical and physiological compartments, which allow distributed and compartmentalized signaling and greatly increase the computational power of single neurons. Superimposed upon this intrinsic compartmental architecture is the subcellular organization of synaptic inputs, which exert local control over the biophysical properties and differentially regulate the input, integration, and output of principal neurons. In the cerebellar cortex, Purkinje neurons are innervated by GABA inhibitory synapses from the stellate and basket cells at dendrites and soma-axon initial (AIS) segments, respectively. Previous studies have shown that an L1 family immunoglobulin cell adhesion molecule (neurofascin186) is distributed as a subcellular gradient and directs basket cell axons to innervate Purkinje cell AIS. Here, we examine the mechanisms underlying the innervation of Purkinje cell dendrites by stellate axons. We found that stellate axons are organized into characteristic trajectories and guided towards Purkinje dendrites by an intermediate scaffold of astroglia—the Bergmann glial (BG) fibers. Another member of L1 family, Close Homologue of L1 (CHL1), is localized to BG fibers and stellate cells, and contributes to the organization of stellate axons along BG fibers and to the innervation of Purkinje cell dendrites.