Development of an anatomical technique for visualizing the mode of climbing fiber innervation in Purkinje cells and its application to mutant mice lacking GluRδ2 and Cav2.1

Miyazaki, Toru; Watanabe, Masahiko

doi:10.1007/s12565-010-0095-1

Cited by 24 publications

(16 citation statements)

References 63 publications

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“…Dextran Alexa 594 (DA-594; Invitrogen) was injected into the inferior olive to label CFs as described (46). After 4 d of survival, mice were fixed by transcardial perfusion and parasagittal cerebellar sections (50 μm in thickness) were cut (11,15,25).…”

Section: Methodsmentioning

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.

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107

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: Methodsmentioning

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.

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107

117

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“…Loss of planarity prior to cell death can also alter synaptic inputs through interdigitation of neighbouring dendritic trees. Multiple climbing fibre (CF) innervation can arise via CF transverse branches (Miyazaki & Watanabe, ) and disruption to the specificity of granule cell input can occur through ascending axons making synaptic contact with more than one Purkinje cell and/or parallel fibres making additional contacts with the same Purkinje cell (Napper & Harvey, ).…”

Section: Introductionmentioning

confidence: 99%

Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

Perkins

Šuminaite

Jackson

2016

The Journal of Physiology

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Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β‐III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin‐R, cell adhesion molecules, metabotropic glutamate receptor‐1 (mGluR1), voltage‐gated sodium channels (Nav) and glutamate transporters. This scaffold of interactions connects β‐III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β‐III spectrin (SPTBN2) underlie SCA type‐5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type‐1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss‐of β‐III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss‐of‐function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing.

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“…A recent morphological study also showed that ectopic CF branches in GluD2 KO mice innervate limited areas in the distal dendritic tree of PCs, and that transverse CF collaterals elongating in the outer molecular layer near the pial surface have glutamatergic terminals around dendrites of multiple neighboring PCs (Miyazaki and Watanabe, 2010). These elongated transverse CF collaterals and ectopic synapse formation occur mutually among neighboring PCs (Miyazaki and Watanabe, 2010). Thus, CFs of GluD2 KO mice are considered to activate their main target PCs through ascending main branches and also neighboring PCs through transverse collaterals.…”

Section: Discussionmentioning

confidence: 99%

“…GluD2 is essential for the formation and stabilization of PF–PC synapses by interacting with Cbln1 that binds to neurexin at PF terminals (Matsuda et al, 2010; Uemura et al, 2010). Thus, the GluD2 knockout (KO) mouse (Kashiwabuchi et al, 1995) has been shown to exhibit various defects in synaptic wiring and neuronal response: (1) the number of PF–PC synapse is reduced to nearly half of that of control mouse, which results in emergence of numerous free spines in PC distal dendrites (Kurihara et al, 1997; Ichikawa et al, 2002; Takeuchi et al, 2005), (2) CFs extend distally along PC dendrites, take over spines from PFs and form ectopic synapses on PC distal dendrites (Ichikawa et al, 2002), (3) transverse collaterals of CFs that run perpendicularly to the plane of PC dendritic tree are markedly elongated and form ectopic synapses on distal dendrites of neighboring PCs along the mediolateral axis (Miyazaki and Watanabe, 2010; Miyazaki et al, 2010), (4) stimulation of the aberrant CFs in cerebellar slices induces atypical excitatory postsynaptic responses with slow rise time and small amplitudes in PCs which are associated with calcium transients localized to distal dendritic arbors (Hashimoto et al, 2001; Miyazaki et al, 2010), and (5) PCs in GluD2 KO mice in vivo exhibit atypical “clustered firing (Cf)” (Yoshida et al, 2004), which is considered to be induced by ectopic CF inputs to PC distal dendrites. Thus, GluD2 KO mice provide an excellent model to study how altered CF to PC wiring affects population activity of PCs and functional microzonal organization in vivo .…”

Section: Introductionmentioning

confidence: 99%

Disruption of cerebellar microzonal organization in GluD2 (GluRδ2) knockout mouse

Hashizume¹,

Miyazaki²,

Sakimura³

et al. 2013

Front. Neural Circuits

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Cerebellar cortex has an elaborate rostrocaudal organization comprised of numerous microzones. Purkinje cells (PCs) in the same microzone show synchronous activity of complex spikes (CSs) evoked by excitatory inputs from climbing fibers (CFs) that arise from neurons in the inferior olive (IO). The synchronous CS activity is considered to depend on electrical coupling among IO neurons and anatomical organization of the olivo-cerebellar projection. To determine how the CF–PC wiring contributes to the formation of microzone, we examined the synchronous CS activities between neighboring PCs in the glutamate receptor δ2 knockout (GluD2 KO) mouse in which exuberant surplus CFs make ectopic innervations onto distal dendrites of PCs. We performed in vivo two-photon calcium imaging for PC populations to detect CF inputs. Neighboring PCs in GluD2 KO mice showed higher synchrony of calcium transients than those in wild-type (control) mice. Moreover, the synchrony in GluD2 KO mice hardly declined with mediolateral separation between PCs up to ~200 μm, which was in marked contrast to the falloff of the synchrony in control mice. The enhanced synchrony was only partially affected by the blockade of gap junctional coupling. On the other hand, transverse CF collaterals in GluD2 KO mice extended beyond the border of microzone and formed locally clustered ectopic synapses onto dendrites of neighboring PCs. Furthermore, PCs in GluD2 KO mice exhibited clustered firing (Cf), the characteristic CF response that was not found in PCs of wild-type mice. Importantly, Cf was often associated with localized calcium transients in distal dendrites of PCs, which are likely to contribute to the enhanced synchrony of calcium signals in GluD2 KO mice. Thus, our results indicate that CF signals in GluD2 KO mice propagate across multiple microzones, and that proper formation of longitudinal olivo-cerebellar projection is essential for the spatiotemporal organization of CS activity in the cerebellum.

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Development of an anatomical technique for visualizing the mode of climbing fiber innervation in Purkinje cells and its application to mutant mice lacking GluRδ2 and Cav2.1

Cited by 24 publications

References 63 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

Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

Disruption of cerebellar microzonal organization in GluD2 (GluRδ2) knockout mouse

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Development of an anatomical technique for visualizing the mode of climbing fiber innervation in Purkinje cells and its application to mutant mice lacking GluRδ2 and Cav2.1

Cited by 24 publications

References 63 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

Cerebellar ataxias: β‐III spectrin's interactions suggest common pathogenic pathways

Disruption of cerebellar microzonal organization in GluD2 (GluRδ2) knockout mouse

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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