Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells

Bosman, Laurens W. J.; Hartmann, Jana; Barski, Jarosław Jerzy; Lepier, Alexandra; Noll‐Hussong, Michael; Reichardt, Louis F.; Konnerth, Arthur

doi:10.1007/s11068-006-9002-z

Cited by 60 publications

(51 citation statements)

References 65 publications

(84 reference statements)

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“…Although several factors crucial for the late phase of CF synapse elimination have been elucidated (12,(16)(17)(18)(19)(41)(42)(43)(44), the molecular bases for the functional differentiation, subsequent dendritic translocation, and the early phase of CF synapse elimination were unclear. The present study demonstrates unequivocally that the P/Q-type VDCC in PCs is crucial for such rearrangements of CF synapses during the first 12 d of postnatal development.…”

Section: Discussionmentioning

confidence: 99%

Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Hashimoto

Teräs

Miyazaki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

117

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Neural circuits are initially redundant but rearranged through activity-dependent synapse elimination during postnatal development. This process is crucial for shaping mature neural circuits and for proper brain function. At birth, Purkinje cells (PCs) in the cerebellum are innervated by multiple climbing fibers (CFs) with similar synaptic strengths. During postnatal development, a single CF is selectively strengthened in each PC through synaptic competition, the strengthened single CF undergoes translocation to a PC dendrite, and massive elimination of redundant CF synapses follows. To investigate the cellular mechanisms of this activity-dependent synaptic refinement, we generated mice with PC-selective deletion of the Ca v 2.1 P/Q-type Ca 2+ channel, the major voltage-dependent Ca 2+ channel in PCs. In the PC-selective Ca v 2.1 knockout mice, Ca 2+ transients induced by spontaneous CF inputs are markedly reduced in PCs in vivo. Not a single but multiple CFs were equally strengthened in each PC from postnatal day 5 (P5) to P8, multiple CFs underwent translocation to PC dendrites, and subsequent synapse elimination until around P12 was severely impaired. Thus, P/Q-type Ca 2+ channels in postsynaptic PCs mediate synaptic competition among multiple CFs and trigger synapse elimination in developing cerebellum.

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Section: Discussionmentioning

confidence: 99%

Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Hashimoto

Teräs

Miyazaki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

117

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“…The action of mGluR1 on climbing fiber synapse elimination is exerted through its downstream effectors G␣ q (the ␣-subunit of the heterotrimeric GTP-binding protein G q ) (Offermanns et al, 1997), PLC␤4 (phospholipase C ␤4) (Kano et al, 1998), and PKC␥ (protein kinase C␥) (Kano et al, 1995). In addition, also neurotrophins have recently been implicated in the maturation of the climbing fiber-Purkinje cell synapses (Bosman et al, 2006;Johnson et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Homosynaptic Long-Term Synaptic Potentiation of the “Winner” Climbing Fiber Synapse in Developing Purkinje Cells

Bosman

Takechi²,

Hartmann³

et al. 2008

J. Neurosci.

101

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During the developmental formation of neuronal circuits, redundant synapses are eliminated and persisting synapses strengthened. In the immature cerebellum, climbing fiber-Purkinje cell synapses undergo a pronounced synaptic rewiring, from a multiple innervation around birth to a mono-innervation in adults. An early stage of this process consists in the differentiation of initially equally strong synapses into one "large" and several "small" synaptic inputs. By performing whole-cell recordings in Purkinje cells of rat cerebellar slices, we found that the coincident activation of a Purkinje cell and one of its afferent climbing fibers induces homosynaptic long-term synaptic potentiation (LTP). This LTP requires postsynaptic Ca 2ϩ signaling and involves an increase in the single channel conductance of the postsynaptic AMPA receptors. Interestingly, LTP occurs exclusively at large synaptic inputs. It is not observed at small inputs that are eventually eliminated. Thus, we identified a new form of LTP that is expressed uniquely and just for a restricted period of early development in the large climbing fiber inputs. Our results suggest that this LTP mediates the activity-dependent maturation of the "winner" climbing fiber.

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“…Indeed, activation of mGluR1 produces a complex postsynaptic response consisting of a calciumrelease signal from intracellular stores and a slow excitatory postsynaptic potential, and long-term depression at parallel fiber-PC synapses is deficient in mGluR1 Ϫ/Ϫ mice (39). The recent finding that inactivation of the neurotrophin receptor, TrkB, slows elimination of climbing fibers (40,41), might reflect altered electrical activity of PCs because inhibitory inputs develop abnormally, but this perturbation could alternatively upset trophic balance in an activity-independent fashion. Perhaps more direct are studies in which harmaline was administered to the inferior olivary nucleus, which contains the cell bodies from which climbing fiber originates.…”

Section: Discussionmentioning

confidence: 99%

Genetic perturbation of postsynaptic activity regulates synapse elimination in developing cerebellum

Lorenzetto

Caselli

Feng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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In many parts of the vertebrate nervous system, synaptic connections are remodeled during early postnatal life. Neural activity plays an important role in regulating one such rearrangement, synapse elimination, in the developing neuromuscular system, but there is little direct evidence on roles of pre-or postsynaptic activity in regulating synapse elimination in the developing brain. To address this issue, we expressed a chloride channel-yellow fluorescent protein fusion in cerebellar Purkinje cells (PCs) of transgenic mice to decrease their excitability. We then assessed elimination of supernumerary climbing fiber inputs to PCs. Individual PCs are innervated by multiple climbing fibers at birth; all but one are eliminated during the first three postnatal weeks in wild-type mice, but multiple innervation persists for at least three months in the transgenic mice. The normal redistribution of climbing fiber synapses from PC somata to proximal dendrites was also blunted in transgenics. These results show that normal electrical activity of the postsynaptic cell is required for it to attain a mature innervation pattern.chloride channel ͉ climbing fiber ͉ Purkinje cell T hroughout the vertebrate nervous system, neurons receive more inputs early in development than they maintain in adulthood. During a circumscribed period in early postnatal life, supernumerary inputs are removed by a process called synapse elimination, and the remaining inputs then become stronger. This process has been analyzed in greatest detail at a peripheral synapse, the skeletal neuromuscular junction, at which all motor axons but one are eliminated, leaving each muscle fiber with a single input. There, the process has been shown to be activity dependent and competitive, with the relative activities of the inputs playing a decisive role in the outcome (1-4).Neural activity also regulates synaptic rearrangements in the developing central nervous system (5-8). In the cerebellar cortex, one of the best-studied systems in this respect, each Purkinje cell (PC) is innervated by multiple climbing fibers at birth. Between postnatal day (P) 5 and P15-20, supernumerary climbing fibers are withdrawn, leaving each PC innervated by just a single climbing fiber (7-10). In parallel, climbing fiber terminations are redistributed on the PC, with a loss of perisomatic synapses and an increase in number of synapses on proximal dendrites (10, 11). Early studies showed that supernumerary climbing fiber inputs were retained in mutants with developmental defects in cerebellar maturation (12)(13)(14)(15), and subsequent analysis demonstrated a critical role for the other main input to PCs, the parallel fibers, in the elimination of redundant inputs (9,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Conversely, harmaline administration to inferior olivary neurons, from which climbing fibers arise, leads to synchronous activation and to the persistence of multiple innervation (26).Limitations of these studies are that most of them involved perturbation of a particular neurotran...

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Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells

Cited by 60 publications

References 65 publications

Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Homosynaptic Long-Term Synaptic Potentiation of the “Winner” Climbing Fiber Synapse in Developing Purkinje Cells

Genetic perturbation of postsynaptic activity regulates synapse elimination in developing cerebellum

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Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells

Cited by 60 publications

References 65 publications

Postsynaptic P/Q-type Ca 2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Postsynaptic P/Q-type Ca 2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Homosynaptic Long-Term Synaptic Potentiation of the “Winner” Climbing Fiber Synapse in Developing Purkinje Cells

Genetic perturbation of postsynaptic activity regulates synapse elimination in developing cerebellum

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Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum