Synapse elimination in olivo-cerebellar explants occurs during a critical period and leaves an indelible trace in Purkinje cells (original) (raw)
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Genetic perturbation of postsynaptic activity regulates synapse elimination in developing cerebellum
Proceedings of the National Academy of Sciences of the United States of America, 2009
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...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008
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 Ca2+ 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. Thu...
During postnatal development, cerebellar climbing fibers strongly innervate a subset of their original Purkinje cell targets and eliminate their connections from the rest. In the adult, each climbing fiber innervates a small number of Purkinje cells and each Purkinje cell is innervated by a single climbing fiber. To get insight about the processes responsible for this remapping, we reconstructed serial electron microscopy datasets from mice during the first postnatal week. In contrast to adult connectivity, individual neonatal climbing fibers innervate many nearby Purkinje cells, and multiple climbing fibers innervate each Purkinje cell. Between postnatal days 3 and 7, Purkinje cells retract long dendrites and grow many proximal dendritic processes. On this changing landscape, individual climbing fibers selectively add many synapses to a subset of Purkinje cell targets in a positive-feedback manner, without pruning synapses from other Purkinje cells. The active zone sizes of synapse...
Scientific reports, 2018
Different afferent synapse populations interact to control the specificity of connections during neuronal circuit maturation. The elimination of all but one climbing-fiber onto each Purkinje cell during the development of the cerebellar cortex is a particularly well studied example of synaptic refinement. The suppression of granule cell precursors by X irradiation during postnatal days 4 to 7 prevents this synaptic refinement, indicating a critical role for granule cells. Several studies of cerebellar development have suggested that synapse elimination has a first phase which is granule cell-independent and a second phase which is granule cell-dependent. In this study, we show that sufficiently-strong irradiation restricted to postnatal days 5 or 6 completely abolishes climbing fiber synaptic refinement, leaving the olivo-cerebellar circuit in its immature configuration in the adult, with up to 5 climbing fibers innervating the Purkinje cell in some cases. This implies that the puta...
Critical period for activity-dependent synapse elimination in developing cerebellum
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
Synapse elimination is considered to be the final step in neural circuit formation, by causing refinement of redundant connections formed at earlier developmental stages. The developmental loss of climbing fiber innervation from cerebellar Purkinje cells is an example of such synapse elimination. It has been suggested that NMDA receptors are involved in the elimination of climbing fiber synapses. In the present study, we probed the NMDA receptor-dependent period of climbing fiber synapse elimination by using daily intraperitoneal injections of the NMDA receptor antagonist MK-801. We found that blockade of NMDA receptors during postnatal day 15 (P15) and P16, but not before or after this period, resulted in a higher incidence of multiple climbing fiber innervation and caused a mild but persistent loss of motor coordination. Neither basic synaptic functions nor cerebellar morphology were affected by this manipulation. Chronic local application of MK-801 to the cerebellum during P15 an...
Activity-dependent plasticity of developing climbing fiber–Purkinje cell synapses
Neuroscience, 2009
Elimination of redundant synapses and strengthening of the surviving ones are crucial steps in the development of the nervous system. Both processes can be readily followed at the climbing fiber to Purkinje cell synapse in the cerebellum. Shortly after birth, around five equally strong climbing fiber synapses are established. Subsequently, one of these five synaptic connections starts to grow in size and synaptic strength, while the others degenerate and eventually disappear. Both the elimination of the redundant climbing fiber synapses and the strengthening of the surviving one depend on a combination of a genetically coded blueprint and synaptic activity. Recently, it has been shown that synaptic activity affects the synaptic strength of developing climbing fibers. Remarkably, the same pattern of paired activity of the presynaptic climbing fiber and the postsynaptic Purkinje cell resulted in strengthening of already "large" climbing fibers and weakening of already "weak" climbing fibers. In this review, we will integrate the current knowledge of synaptic plasticity of climbing fibers with that of other processes affecting climbing fiber development.
Dendritic Translocation Establishes the Winner in Cerebellar Climbing Fiber Synapse Elimination
The Journal of Neuroscience, 2013
In many regions of the developing mammalian nervous system, functional synaptic circuitry is formed by competitive elimination of early formed redundant synapses. However, how winning synapses emerge through competition remains unclear in the brain largely because of the technical difficulty of directly observing this dynamic cellular processin vivo. Here, we developed a method of two-photon multicolor vital imaging to observe competitive elimination of supernumerary climbing fibers (CFs) in the cerebellum of live mouse pups. At birth, each Purkinje cell (PC) in the cerebellar cortex is innervated by multiple CFs; an activity-dependent regression of supernumerary CFs ultimately yields a single innervation for most PCs by postnatal day 21. As supernumerary CFs are pruned, the terminal field of CFs translocates from the soma to the dendrites of PCs.In vivotime-lapse imaging of CF elimination revealed that (1) CF terminals were highly motile on the soma, but their motility was signific...