Reinnervation of Late Postnatal Purkinje Cells by Climbing Fibers: Neosynaptogenesis without Transient Multi-Innervation

Abstract

Synaptic partner selection and refinement of projections are important in the development of precise and functional neuronal connections. We investigated the formation of new synaptic connections in a relatively mature system to test whether developmental events can be recapitulated at later stages (i.e., after the mature synaptic organization has been established), using a model of postlesional reinnervation in the olivo-cerebellar pathway.During the development of this pathway, synaptic connections between climbing fibers (CFs) and Purkinje cells (PCs) are diffuse and redundant before synapse elimination refines the pattern. The regression of CFs during the first 2 postnatal weeks in the rat leads to mono-innervation of each PC. After unilateral transection of the rat olivo-cerebellar pathway and intracerebellar injection of BDNF 24 h after lesion, axons from the remaining inferior olive can sprout into the deafferented hemicerebellum and establish new contacts with denervated PCs at later developmental stages. We found that these contacts are first established on somatic thorns before the CFs translocate to the PC dendrites, recapitulating the morphological steps of normal CF-PC synaptogenesis, but on a relatively mature PC.However, electrophysiology of PC reinnervation by transcommissural CFs in these animals showed that each PC is reinnervated by only one CF. This mono-innervation contrasts with the reinnervation of grafted immature PCs in the same cerebellum. Our results provide evidence that relatively mature PCs do not receive several olivary afferents during late reinnervation, suggesting a critical role of the target cell state in the control of CF-PC synaptogenesis. Thus, synapse exuberance and subsequent elimination are not a prerequisite to reach a mature relationship between synaptic partners.

Mature Purkinje Cells Require the Retinoic Acid-Related Orphan Receptor-α (RORα) to Maintain Climbing Fiber Mono-Innervation and Other Adult Characteristics

“…Transcription factors drive the developmental acquisition of mature neuronal features (Polleux et al, 2007;Hobert, 2011). Some of these transcription factors maintain their expression into adulthood.…”

Differential expression of TrkB isoforms switches climbing fiber‐Purkinje cell synaptogenesis to selective synapse elimination

“…Indeed, BDNF neutralization and TrkB.T overexpression induce dismantling of immature synapses (Luikart and Parada, 2006). Furthermore, in mature CFs that have already downregulated their TrkB.FL (this study; Riva-Depaty et al, 1998), BDNF only induces mono-reinnervation (Letellier et al, 2007). Therefore, the TrkB developmental expression profile we observed plus the limited synaptogenic response of mature CFs expressing the truncated rather than full length receptor, are not compatible with TrkB signaling directing CF regression; rather they imply that reduced synaptogenic drive becomes permissive to synapse elimination.…”

“…active synaptogenesis), the majority of TrkB signaling is in CF terminals. The role of TrkB signaling in CF-PC synaptogenesis is confirmed by the absence of reinnervating CF-PC neosynaptogenesis when this signaling is disrupted, and the capacity for exogenous BDNF to increase CF reinnervation after Px3 (Willson et al, 2008) and induce reinnervation in the mature system (Dixon and Sherrard, 2006;Letellier et al, 2007).…”

Faire et refaire une synapse en choisissant un partenaire

“…synaptiques spécifiques et fonctionnels après une lésion [11][12][13]. De façon plus surprenante, ces travaux montrent que le processus de réinnervation postlésionnelle conduit à la mono-innervation des cellules de Purkinje matures, alors que ces cellules sont en principe incapables d'éliminer des fibres grimpantes surnuméraires après la fin de la période critique [3,12].…”

“…De façon plus surprenante, ces travaux montrent que le processus de réinnervation postlésionnelle conduit à la mono-innervation des cellules de Purkinje matures, alors que ces cellules sont en principe incapables d'éliminer des fibres grimpantes surnuméraires après la fin de la période critique [3,12]. Ces études ont montré que la maturation neuronale empêche l'établissement de connexions synaptiques redondantes en favorisant l'établissement de connexions précises d'emblée (mono-innervation directe).…”