Brain-derived neurotrophic factor induces post-lesion transcommissural growth of olivary axons that develop normal climbing fibers on mature Purkinje cells

Dixon, Kirsty J.; Sherrard, Rachel M.

doi:10.1016/j.expneurol.2006.05.010

Cited by 31 publications

(31 citation statements)

References 85 publications

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“…In this study, we induced CF reinnervation with injections of BDNF into the denervated hemivermis of rats pedunculotomized at P15 (Dixon and Sherrard, 2006). Our results show that functional synapses form rapidly on the PC soma and thereafter translocate to the dendrites during the first week of reinnervation.…”

Section: Introductionmentioning

confidence: 90%

“…Cerebellar parasagittal slices (200 m thick) from the left hemivermis were prepared as described previously (Llano et al, 1991) from normal and pedunculotomized/BDNF-injected rats between 2 and 6 DPI and from grafted, pedunculotomixed, and BDNF-injected rats between 2 and 4 DPI. We recorded from PCs in the same region of the cerebellar vermis (within 1 mm from the midline) as the anatomical studies because it is consistently reinnervated (Dixon and Sherrard, 2006). We made whole-cell patch-clamp recordings from PCs using an upright microscope (BX50WI; Olympus France, Rungis, France) at 20°C.…”

Section: Methodsmentioning

confidence: 99%

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

Letellier¹,

Bailly²,

Demais³

et al. 2007

J. Neurosci.

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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.

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Section: Introductionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

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

Letellier¹,

Bailly²,

Demais³

et al. 2007

J. Neurosci.

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“…Plasticity within the olivocerebellar pathway can be induced by cutting it unilaterally (pedunculotomy: Px) in rodents and injecting neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) [8], into the denervated hemicerebellum. This stimulates the remaining (ipsilateral) ION to grow a new pathway, which reinnervates the denervated hemicerebellum [8,9]. The induced reinnervation is incomplete but respects the parasagittal organisation [8] and supports recovery of motor and spatial function [9].…”

Section: Introductionmentioning

confidence: 99%

What Does Low-Intensity rTMS Do to the Cerebellum?

Morellini

Grehl²,

Tang³

et al. 2014

Cerebellum

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Non-invasive stimulation of the human cerebellum, such as by transcranial magnetic stimulation (TMS), is increasingly used to investigate cerebellar function and identify potential treatment for cerebellar dysfunction. However, the effects of TMS on cerebellar neurons remain poorly defined. We applied low-intensity repetitive TMS (LI-rTMS) to the mouse cerebellum in vivo and in vitro and examined the cellular and molecular sequelae. In normal C57/Bl6 mice, 4 weeks of LI-rTMS using a complex biomimetic high-frequency stimulation (BHFS) alters Purkinje cell (PC) dendritic and spine morphology; the effects persist 4 weeks after the end of stimulation. We then evaluated whether LI-rTMS could induce climbing fibre (CF) reinnervation to denervated PCs. After unilateral pedunculotomy in adult mice and 2 weeks sham or BHFS stimulation, VGLUT2 immunohistochemistry was used to quantify CF reinnervation. In contrast to sham, LI-rTMS induced CF reinnervation to the denervated hemicerebellum. To examine potential mechanisms underlying the LI-rTMS effect, we verified that BHFS could induce CF reinnervation using our in vitro olivocerebellar explants in which denervated cerebellar tissue is co-cultured adjacent to intact cerebella and treated with brain-derived neurotrophic factor (BDNF) (as a positive control), sham or LI-rTMS for 2 weeks. Compared with sham, BDNF and BHFS LI-rTMS significantly increased CF reinnervation, without additive effect. To identify potential underlying mechanisms, we examined intracellular calcium flux during the 10-min stimulation. Complex high-frequency stimulation increased intracellular calcium by release from intracellular stores. Thus, even at low intensity, rTMS modifies PC structure and induces CF reinnervation.

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“…In the pedunculotomised anti-BDNF treated (2 lg/ mL) hemicerebellum, VGLUT2-like immunoreactivity (VGLUT2-IR: n ¼ 4) was present as discrete patches throughout the granular layer but was largely absent from the molecular layer [ Fig. 6(B)], consistent with mossy terminals but no CFs (Dixon and Sherrard, 2006;Hioki et al, 2003). In all animals analyzed, VGLUT2-labeled CF terminals were never observed within or immediately adjacent to the anti-BDNF injection site in VIb/crus I to VII/paramedian lobule [ Fig.…”

Section: No Transcommissural Climbing Fiber Reinnervation When Trkb Smentioning

confidence: 86%

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

Sherrard¹,

Dixon²,

Bakouche³

et al. 2009

Developmental Neurobiology

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Correct neural function depends on precisely organized connectivity, which is refined from broader projections through synaptic/collateral elimination. In the rat, olivocerebellar topography is refined by regression of multiple climbing fiber (CF) innervation of Purkinje cells (PC) during the first two postnatal weeks. The molecules that initiate this regression are not fully understood. We assessed the role of cerebellar neurotrophins by examining tropomycin receptor kinase (Trk) receptor expression in the inferior olive and cerebellum between postnatal days (P)3-7, when CF-PC innervation changes from synapse formation to selective synapse elimination, and in a denervation-reinnervation model when synaptogenesis is delayed. Trks A, B, and C are expressed in olivary neurons; although TrkA was not transported to the cerebellum and TrkC was unchanged during innervation and reinnervation, suggesting that neither receptor is involved in CF-PC synaptogenesis. In contrast, both total and truncated TrkB (TrkB.T) increased in the olive and cerebellum from P4, whereas full-length and activated phosphorylated TrkB (phospho-TrkB) decreased from P4-5. This reveals less TrkB signaling at the onset of CF regression. This expression pattern was reproduced during CF-PC reinnervation: in the denervated hemicerebellum phosphoTrkB decreased as CF terminals degenerated, then increased in parallel with the delayed neosynaptogenesis as new CFs reinnervated the denervated hemicerebellum. In the absence of this signaling, CF reinnervation did not develop. Our data reveal that olivocerebellar TrkB activity parallels CF-PC synaptic formation and stabilization and is required for neosynaptogenesis. Furthermore, TrkB.T expression rises to reduce TrkB signaling and permit synapse elimination. ' 2009 Wiley Periodicals, Inc. Develop Neurobiol 69: 897-912, 2009

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Brain-derived neurotrophic factor induces post-lesion transcommissural growth of olivary axons that develop normal climbing fibers on mature Purkinje cells

Cited by 31 publications

References 85 publications

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

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

What Does Low-Intensity rTMS Do to the Cerebellum?

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

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