Verslag – Rapport – Bericht – Report - GSKE - FMRE

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3 Additional projects and collaborations based on expertise developed under the frame of this program. We previously characterized the distribution of the basal ganglia-specific synaptic protein SV2C by showing that it is highly expressed in dopaminergic neurons, in striatal cholinergic interneurons and, at a moderate level, in both MSN subpopulations (Dardou et al., 2011). We have now investigated the implication of SV2C in both normal and pathological basal ganglia functioning. We showed that in SV2Cdeficient mice (SV2C -/- ) mice, the expression of tyrosine hydroxylase mRNA in midbrain dopaminergic neurons was largely and significantly increased whilst enkephalin mRNA expression was significantly decreased in the caudate-putamen and accumbens nucleus (Dardou et al., 2012). In two models of dopaminergic denervation, SV2C mRNA expression was significantly increased in the striatum. In order to further understand the role of SV2C, we performed behavioural experiments on SV2C -/- mice and on knock-down mice receiving an injection of adeno-associated virus expressing SV2C miRNA specifically in the ventral midbrain. We showed that even if these modifications of SV2C expression had no impact on behaviour in open field and elevated plus maze, the specific knock-down of SV2C expression in the dopaminergic neurons completely abolished the development of a conditioned place preference induced by cocaine while the reaction to an acute drug injection remains similar in these mice compared to control mice (Dardou et al., 2012). These results suggest that SV2C is involved in normal operation of the basal ganglia network and could also be involved in system adaptation in basal ganglia pathological conditions. In collaboration with the group of Martin Schwab from the Brain Research Institute at University of Zurich, we investigated the function of neuronal Nogo-A. Nogo-A is a membrane protein enriched in the adult central myelin, where it restricts the capacity of axons to grow and regenerate after injury but is also expressed by certain neurons, in particular during development, where its physiological function was less well understood. In the cerebellum, Nogo-A is transitorily highly expressed in the Purkinje cells (PC) during early postnatal development. By using Nogo-A-deficient (Nogo-A -/- ) mice and mice with a selective overexpression of Nogo-A in PC and patch clamp recordings as well as 3D confocal reconstruction of recorded PC, we analyzed its effect on dendritogenesis and on the formation of their main input synapses from parallel (PF) and climbing fibers (CF). PC dendritic trees were larger and more complex in Nogo-A -/- mice and smaller than in wild-type in Nogo-A overexpressing PC. Nogo-A -/- resulted in premature soma-to-dendrite translocation of CF and an enlargement of the CF territory in the molecular layer during development. Although spine density was not influenced by Nogo-A, the size of postsynaptic densities of PF-PC synapses was negatively correlated with the Nogo-A expression level. Moreover, PC patch clamp recordings revealed that Nogo-A negatively regulates the strength of synaptic transmission at the PF-PC synapse. Thus, our results demonstrated that Nogo-A is a negative regulator of PC input synapses which orchestrates cerebellar connectivity through regulation of synapse morphology and size of the PC dendritic tree. They identified Nogo-A as a putative negative controller of synaptic development, strength and structure in several brain regions. We took part to the study of Jens Eilers and collaborators from the Carl-Ludwig Institute for Physiology at University of Leipzig on the coupling between presynaptic Ca 2+ and transmitter release and hence synaptic transmission (Schmidt et al., 2012). The coupling distance between presynaptic Ca 2+ influx and the sensor for vesicular transmitter release determines speed and reliability of synaptic transmission. We have analyzed excitatory PF to PC synapses in the cerebellum of wild-type mice and mice deficient in the Ca 2+ binding protein calretinin, specifically expressed in the granule cell and their axons (PF) (Schiffmann et al., 1999). The coupling distance was quantified by combining fluctuation analyses in 76 Verslag – Rapport – Report 2012
patch clamp recordings, presynaptic Ca 2+ imaging, and reaction-diffusion computer simulations. We found a coupling distance of
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Verslag - Rapport - Bericht - Repor
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Fondation Médicale Reine Elisabeth
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Onderzoeksprogramma’s gefinancier
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Progress reports of the university
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Progress report of the research gro
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ß-actin in neural crest cell migra
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In addition whole mount in situ hyb
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In summary we show an essential rol
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Progress report of the research gro
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mRNA metabolism at synapses and spi
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eIF4E upon DHPG stimulation, but Ra
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REFERENCES - Bagni, C., Tassone, F.
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