Homosynaptic long-term synaptic potentiation of the "winner" climbing fiber synapse in developing Purkinje cells (original) (raw)
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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.
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...
Long-Term Depression of the Cerebellar Climbing Fiber–Purkinje Neuron Synapse
Neuron, 2000
first 3 weeks of postnatal life in the rat, an activity-Baltimore, Maryland 21205 dependent refinement occurs such that each Purkinje † Department of Anatomy neuron receives a single CF (Cré pel et al., 1976; Lohof Erasmus University Rotterdam et al., 1996), which is nonetheless extremely powerful, 3000 DR, Rotterdam as it comprises 0051ف release sites (Strata and Rossi, The Netherlands 1998). Activation of the CF leads to a stereotyped membrane response in the Purkinje neuron, which has an all-or-none character (Eccles et al., 1966). These so-Summary called "complex spikes" result from an AMPA receptormediated depolarization, thereby initiating Na ϩ action In classic Marr-Albus-Ito models of cerebellar funcpotentials in the axon that spread passively into the tion, coactivation of the climbing fiber (CF) synapse, dendritic tree (Stuart and Hä usser, 1994). The somatic which provides massive, invariant excitation of Pur-Na ϩ spikes are followed by a series of diminishing spikekinje neurons (coding the unconditioned stimulus), tolets produced mainly by dendritic Ca 2ϩ influx (Lliná s and Sugimori, 1980a, 1980b). In contrast to the CFs, parallel gether with a graded parallel fiber synaptic array (codfibers, which are the axons of cerebellar granule neuing the conditioned stimulus) leads to long-term rons, each make contact with many Purkinje neurons. depression (LTD) of parallel fiber-Purkinje neuron syn-Due to the vast numbers of granule neurons, and their apses, underlying production of a conditioned redivergent input to Purkinje neurons (each receives sponse. Here, we show that the supposedly invariant 000,002ف parallel fiber contacts), this synapse is the CF synapse can also express LTD. Brief 5 Hz stimulamost abundant in the vertebrate central nervous system. tion of the CF resulted in a sustained depression of Activation of single parallel fibers also produces depo-CF EPSCs that did not spread to neighboring parallel larization mediated by AMPA receptors, but this depofiber synapses. Like parallel fiber LTD, CF LTD required larization is typically small and thereby contributes to postsynaptic Ca 2؉ elevation, activation of group 1 the overall rate of Na ϩ spiking (called "simple spiking"). mGluRs, and activation of PKC. CF LTD is potentially Beginning in the 1960s, models of cerebellar network relevant for models of cerebellar motor control and function have suggested that the parallel fiber-Purkinje learning and the developmental conversion from multineuron synapse might be modifiable in a use-dependent ple to single CF innervation of Purkinje neurons. fashion, and that such plasticity might underlie certain forms of motor learning. In these models proposed by
Modulation, Plasticity and Pathophysiology of the Parallel Fiber-Purkinje Cell Synapse
Frontiers in synaptic neuroscience, 2016
The parallel fiber-Purkinje cell (PF-PC) synapse represents the point of maximal signal divergence in the cerebellar cortex with an estimated number of about 60 billion synaptic contacts in the rat and 100,000 billions in humans. At the same time, the Purkinje cell dendritic tree is a site of remarkable convergence of more than 100,000 parallel fiber synapses. Parallel fiber activity generates fast postsynaptic currents via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and slower signals, mediated by mGlu1 receptors, resulting in Purkinje cell depolarization accompanied by sharp calcium elevation within dendritic regions. Long-term depression (LTD) and long-term potentiation (LTP) have been widely described for the PF-PC synapse and have been proposed as mechanisms for motor learning. The mechanisms of induction for LTP and LTD involve different signaling mechanisms within the presynaptic terminal and/or at the postsynaptic site, promoting enduring modificat...
Journal of Neuroscience, 2010
(PF) synapse formation, elimination of surplus climbing fibers (CFs), long-term depression, motor coordination, and motor learning. To address its role in adulthood, we previously developed a mouse model of drug-induced GluR␦2 ablation in adult PCs . In that study, we demonstrated an essential role to maintain the connectivity of PF-PC synapses, based on the observation that both mismatching of presynaptic and postsynaptic specializations and disconnection of PF-PC synapses are progressively increased after GluR␦2 ablation. Here, we pursued its role for CF wiring in adult cerebellum. In parallel with the disconnection of PF-PC synapses, ascending CF branches exhibited distal extension to innervate distal dendrites of the target and neighboring PCs. Furthermore, transverse CF branches, a short motile collateral rarely forming synapses in wild-type animals, displayed aberrant mediolateral extension to innervate distal dendrites of neighboring and remote PCs. Consequently, many PCs were wired by single main CF and other surplus CFs innervating a small part of distal dendrites. Electrophysiological recording further revealed that surplus CF-EPSCs characterized with slow rise time and small amplitude emerged after GluR␦2 ablation, and increased progressively both in number and amplitude. Therefore, GluR␦2 is essential for maintaining CF monoinnervation in adult cerebellum by suppressing aberrant invasion of CF branches to the territory of PF innervation. Thus, GluR␦2 fuels heterosynaptic competition and gives PFs the competitive advantages over CFs throughout the animal's life.
Proceedings of the National Academy of Sciences, 2009
During developmental synaptogenesis, the pre-and postsynaptic cells undergo specific interactions that lead to the establishment of the mature circuit. We have studied the roles of the pre-and postsynaptic cells in establishing this mature innervation by using an in vitro model of synaptic development. We describe climbing fiber (CF)-Purkinje cell (PC) synaptogenesis in cultured mouse hindbrain explants and show that synaptic competition occurs during early development in vitro. By manipulating the maturation stage of each of the synaptic partners in a coculture experimental paradigm, we found that multi-innervation does not occur when both synaptic partners are mature and have already experienced synapse elimination; in contrast, mature PCs can be multi-innervated when they have never experienced synapse elimination and/or when CFs are immature. However in these cases, the normal process of synapse elimination is impaired. These results show that CF-synapse elimination occurs only during a PC-dependant critical period and triggers indelible signals that prevent synapse competition in the mature system. cerebellum ͉ climbing fiber ͉ coculture ͉ synapse competition ͉ synaptogenesis Author contributions: M.L., J.M., and A.M.L. designed research; M.L. and R.W. performed research; M.L. analyzed data; and M.L., J.M., and A.M.L. wrote the paper.
Journal of Neuroscience, 2010
plasticity raises the spontaneous spike frequency of Purkinje cells. The latter effect does not impair tonic spike firing in the target neurons of inhibitory Purkinje cell projections in the deep cerebellar nuclei, but lowers the Purkinje cell signal-to-noise ratio, thus reducing the PF readout. These observations suggest that intrinsic plasticity accompanies LTP of active PF synapses, while it reduces at weaker, nonpotentiated synapses the probability for subsequent potentiation and lowers the impact on the Purkinje cell output.
Neuroscience, 2003
Pattern of activity during development is important for the refinement of the final architecture of the brain. In the cerebellar cortex, the regression from multiple to single climbing fiber innervation of the Purkinje cell occurs during development between postnatal days (P) 5 and 15. However, the regression is hampered by altering in various ways the morpho-functional integrity of the parallel fiber input. In rats we disrupted the normal activity pattern of the climbing fiber, the terminal arbor of the inferior olive neurons, by administering harmaline for 4 days from P9 to P12. At all studied ages (P15-87) after harmaline treatment multiple (double only) climbing fiber EPSC-steps persist in 28% of cells as compared with none in the control. The ratio between the amplitudes of the larger and the smaller climbing fiber-evoked EPSC increases in parallel with the decline of the polyinnervation factor, indicating a gradual enlargement of the synaptic contribution of the winning climbing fiber synapse at the expense of the losing one. Harmaline treatment had no later effects on the climbing fiber EPSC kinetics and I/V relation in Purkinje cells (P15-36). However, there was a rise in the paired-pulse depression indicating a potentiation of the presynaptic mechanisms. In the same period, after harmaline treatment, parallel fiber-Purkinje cell electrophysiology was unaffected. The distribution of parallel fiber synaptic boutons was also not changed. Thus, a change in the pattern of activity during a narrow developmental period may affect climbing fiber-Purkinje cell synapse competition resulting in occurrence of multiple innervation at least up to 3 months of age. Our results extend the current view on the role of the pattern of activity in the refinement of neuronal connections during development. They suggest that many similar results obtained by different gene or receptor manipulations might be simply the consequence of disrupting the pattern of activity.