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

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.

The cell adhesion molecule CHL1 interacts with patched-1 to regulate apoptosis during postnatal cerebellar development

“…Absence of CHL1 may lead to enhanced proliferation and differentiation of granule cells via SHH, resulting in deficient innervation of stellate and Purkinje cells, aberrant branching and orientation of stellate cell axons and aberrant arborizations of Purkinje cell dendrites (Ango et al, 2008;Jakovcevski et al, 2009). Defective innervation of Purkinje cell dendrites by granule cell axons in CHL1-deficient mice would be likely to cause loss of Purkinje cells.…”

“…The cell adhesion molecule CHL1 (Holm et al, 1996;Hillenbrand et al, 1999) contributes to these developmental events, and ablation of CHL1 in mice results in malformation of brain structures (Montag-Sallaz et al, 2002;Demyanenko et al, 2004Demyanenko et al, , 2011Nikonenko et al, 2006;Wright et al, 2007;Ango et al, 2008;Jakovcevski et al, 2009). In the cerebellum, CHL1 deficiency leads to aberrant branching, orientation and targeting of cerebellar stellate cell axons as well as loss of cerebellar Purkinje and granule cells (Ango et al, 2008;Jakovcevski et al, 2009).…”

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…Cells that arrive later in the molecular layer and settle more superWcially, and would Wnd only more distal dendrites free to innervate. A twist to this story is added by the Wnding that developmental interaction between Purkinje cells and their aVerent inhibitory neurons is mediated, or at least modulated, by Bergmann astroglial cells (Ango et al 2008). …”

Neural Activity and Neurotransmission Regulate the Maturation of the Innervation Field of Cortical GABAergic Interneurons in an Age-Dependent Manner

“…Recent studies have started to elucidate the mechanisms regulating the maturation of GABAergic innervation. For example, it has been shown that target selection is mainly regulated by molecular cues (Ango et al, 2004(Ango et al, , 2008, while synapse proliferation is dependent on neural activity levels and GABAergic neurotransmission (Chattopadhyaya et al, 2004. Our knowledge of the molecular mechanisms mediating activity-dependent GABAergic synapse proliferation has also improved; indeed, recent studies identified several factors that either stimulate (e.g., BDNF, GAD67, NCAM; for review, see Huang et al, 2007) or inhibit (polysialated-NCAM; Di ) the formation of perisomatic GABAergic innervation.…”