Cerebellar synaptogenesis: what we can learn from mutant mice

Examination of perturbations in the adult cerebellar connectivity, that follow well-defined lesions produced by gene mutations in the mouse, reveals a few of the numerous and intricate cellular interactions taking place during synaptogenesis. In weaver and in the central ectopia of reeler, Purkinje cells form innumerable dendritic spines, despite the absence of parallel fibers. Only a small proportion of these spines are innervated, and their presynaptic partners are mossy fibers (heterologous synapses) originating from spinal cord, but not from pontine nuclei. Hence, the early phase of membrane recognition is based more on a hierarchical choice between a wide range of graded preferences, than on the complementarity of a narrow range of synaptic affinities. The comparative analysis of weaver, reeler, staggerer and hyperspiny Purkinje cell has allowed us to establish that the late phase of synapse stabilization or elimination, leading to the numerical matching of one climbing fiber per Purkinje cell, is not based on climbing fiber translocation. Conversely, this regression appears to be the result of a process of competition between climbing fibers and parallel fibers. Whatever the mechanisms of the competition are, the results obtained with the mutants suggest that activity of the forming cerebellar circuitry is involved in their regulation. Finally, a new mutation is reported, the nodding mouse, to illustrate the fact that the ultimate morphology of presynaptic boutons results from an interplay between intrinsically regulated factors (features of presynaptic organelles) and the morphogenetic influence of postsynaptic partners. This accounts for the size and shape of the boutons as well as for the class of synaptic junction. Furthermore, this morphogenetic influence is not restricted to early life but occurs whenever the originally established balance between pre- and postsynaptic elements is upset.

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Electron microscopic localization of neuron-specific enolase in rat and mouse brain.

Journal of Histochemistry & Cytochemistry ◽

10.1177/32.12.6389693 ◽

1984 ◽

Vol 32 (12) ◽

pp. 1295-1302 ◽

Cited By ~ 59

Author(s):

S A Vinores ◽

M M Herman ◽

L J Rubinstein ◽

P J Marangos

Keyword(s):

Purkinje Cell ◽

Vascular Endothelial Cells ◽

Intracellular Localization ◽

Neuron Specific Enolase ◽

Mossy Fibers ◽

Electron Microscopic ◽

Myelinated Axons ◽

Parallel Fibers ◽

The Brain ◽

Purkinje Cell Dendrites

The cellular distribution and intracellular localization of neuron-specific enolase (NSE) has been studied by electron microscopic immunocytochemistry in the brain of the rat and of the mouse. Although the intensity of staining was less in the mouse, the same structures were positive in both species. In the cerebrum, the neuronal perikarya and dendrites were intensely stained, but staining was almost entirely absent in the presynaptic terminals. The deep neurons of the brain stem were also positive. In the cerebellum, perikarya, axons, and parallel fibers of the granule cell neurons were stained as were the synaptic vesicles and presynaptic membranes of the synapses between the parallel fibers and the Purkinje cell dendrites. Golgi cell dendrites, basket cells and their axons, and mossy fibers were also positive. In contrast, the Purkinje cells including their dendrites, and the climbing fibers that formed synapses with the Purkinje cell dendrites were not stained. The majority of the myelinated axons in both the cerebrum and the cerebellum did not stain, but the fibrillary astrocytic processes between myelinated axons in the white matter did. Oligodendroglia, protoplasmic astrocytes, Bergmann glia, astrocytes investing capillaries, and vascular endothelial cells were negative for reaction product. In the positively staining cells and their processes, the positivity was dispersed throughout the cytoplasm and corresponded most closely to the distribution of ribosomes, the granular endoplasmic reticulum, and microtubules. Nuclei, mitochondria, the cisternae of the Golgi complex, myelin lamellae, and most membranes were not stained.

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Activity-Dependent Gating of Calcium Spikes by A-type K+ Channels Controls Climbing Fiber Signaling in Purkinje Cell Dendrites

Neuron ◽

10.1016/j.neuron.2014.08.035 ◽

2014 ◽

Vol 84 (1) ◽

pp. 137-151 ◽

Cited By ~ 36

Author(s):

Yo Otsu ◽

Païkan Marcaggi ◽

Anne Feltz ◽

Philippe Isope ◽

Mihaly Kollo ◽

...

Keyword(s):

Purkinje Cell ◽

Climbing Fiber ◽

Calcium Spikes ◽

K Channels ◽

Type K ◽

Activity Dependent ◽

Purkinje Cell Dendrites

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Activity-dependent plasticity of developing climbing fiber–Purkinje cell synapses

Neuroscience ◽

10.1016/j.neuroscience.2009.01.032 ◽

2009 ◽

Vol 162 (3) ◽

pp. 612-623 ◽

Cited By ~ 29

Author(s):

L.W.J. Bosman ◽

A. Konnerth

Keyword(s):

Purkinje Cell ◽

Climbing Fiber ◽

Dependent Plasticity ◽

Activity Dependent

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Climbing Fiber Function: Regulation of Purkinje Cell Responsiveness

Proceedings in Life Sciences - Cerebellar Functions ◽

10.1007/978-3-642-69980-1_17 ◽

1984 ◽

pp. 247-259

Author(s):

J. R. Bloedel ◽

T. J. Ebner

Keyword(s):

Purkinje Cell ◽

Climbing Fiber

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Selective stabilization and elimination of climbing fiber- Purkinje cell synapse in the developing cerebellum: Signal transduction and critical period.

ZOOLOGICAL SCIENCE ◽

10.2108/zsj.19.1404 ◽

2002 ◽

Vol 19 (12) ◽

pp. 1404-1405

Author(s):

S KAKIZAWA

Keyword(s):

Signal Transduction ◽

Purkinje Cell ◽

Critical Period ◽

Climbing Fiber ◽

Selective Stabilization ◽

Developing Cerebellum ◽

Cell Synapse

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Proximal Myopathy due to m.5835G>A Mutation in Mitochondrial MT-TY Gene

Case Reports in Neurological Medicine ◽

10.1155/2018/8406712 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

C. Simoncini ◽

V. Montano ◽

G. Alì ◽

R. Costa ◽

G. Siciliano ◽

...

Keyword(s):

Clinical Phenotype ◽

Gene Mutations ◽

Mitochondrial Diseases ◽

Leigh Syndrome ◽

Phenotype Correlation ◽

Mitochondrial Trna ◽

Gene Coding ◽

Clinical Presentations ◽

Wide Range ◽

Proximal Myopathy

Mitochondrial (mt) tRNA (MTT) gene mutations are an important cause of mitochondrial diseases and are associated with a wide range of clinical presentations. Most mutations fall into three mitochondrial tRNAs (tRNAIle, tRNALeu (UUR), and tRNALys) and are responsible for half of the mitochondrial diseasees associated with tRNA mutation, with MERRF, MELAS, mitochondrial myopathy, and Leigh syndrome being the most frequent phenotypes. More than 100 tRNA pathogenetic mutations are described, showing little correlation between the observed clinical phenotype and a specific mitochondrial tRNA mutation. Furthermore different mutation can manifest with similar clinical phenotypes, making the genotype-phenotype correlation difficult. Here we report the case of an Italian 53-year-old woman presenting with a proximal myopathy and the m.5835G>A mutation in MT-TY gene coding for the mitochondrial tRNA Tyrosine gene.

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Target neuron controls the integrity of afferent axon phenotype: a study on the Purkinje cell-climbing fiber system in cerebellar mutant mice

Journal of Neuroscience ◽

10.1523/jneurosci.15-03-02040.1995 ◽

1995 ◽

Vol 15 (3) ◽

pp. 2040-2056 ◽

Cited By ~ 56

Author(s):

F Rossi ◽

A Jankovski ◽

C Sotelo

Keyword(s):

Purkinje Cell ◽

Climbing Fiber ◽

Mutant Mice ◽

Fiber System ◽

Target Neuron ◽

Cerebellar Mutant

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The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz055 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Jiaojiao Deng ◽

Lingyang Hua ◽

Tao Han ◽

Mi Tian ◽

Daijun Wang ◽

...

Keyword(s):

Binding Protein ◽

Gene Mutations ◽

Therapeutic Effects ◽

Creb Binding Protein ◽

Cycle Arrest ◽

Large Patient ◽

Wide Range ◽

Patient Series ◽

Responsive Element

Abstract Background Meningiomas with Neurofibromin 2 gene mutations (NF2-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease. Methods Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort (n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee (NF2 wildtype) and CH157-MN (NF2 deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in NF2-mutant meningiomas were further characterized in vitro and in patient-derived xenograft (PDX) models. Results Low Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of NF2-mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2-mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling. Conclusions This study highlights the importance of ligand-mediated Wnt/β-catenin signaling as well as its drugable potency in NF2-mutant meningioma.

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Construction of 3D Cellular Composites with Stem Cells Derived from Adipose Tissue and Endothelial Cells by Use of Optical Tweezers in a Natural Polymer Solution

Materials ◽

10.3390/ma12111759 ◽

2019 ◽

Vol 12 (11) ◽

pp. 1759 ◽

Cited By ~ 1

Author(s):

Takehiro Yamazaki ◽

Toshifumi Kishimoto ◽

Paweł Leszczyński ◽

Koichiro Sadakane ◽

Takahiro Kenmotsu ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Adipose Tissue ◽

Optical Tweezers ◽

Single Cells ◽

Three Dimensional ◽

Cell Types ◽

Cellular Interactions ◽

Research Fields ◽

Wide Range

To better understand the regulation and function of cellular interactions, three-dimensional (3D) assemblies of single cells and subsequent functional analysis are gaining popularity in many research fields. While we have developed strategies to build stable cellular structures using optical tweezers in a minimally invasive state, methods for manipulating a wide range of cell types have yet to be established. To mimic organ-like structures, the construction of 3D cellular assemblies with variety of cell types is essential. Our recent studies have shown that the presence of nonspecific soluble polymers in aqueous solution is the key to creating stable 3D cellular assemblies efficiently. The present study further expands on the construction of 3D single cell assemblies using two different cell types. We have successfully generated 3D cellular assemblies, using GFP-labeled adipose tissue-derived stem cells and endothelial cells by using optical tweezers. Our findings will support the development of future applications to further characterize cellular interactions in tissue regeneration.

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