Amelioration of the Behavioral Phenotype in Genetically Ataxic Mice through Bilateral Intracerebellar Grafting of Fetal Purkinje Cells

1996 ◽  
Vol 5 (2) ◽  
pp. 269-277 ◽  
Author(s):  
Lazaros C. Triarhou ◽  
Zei Zhang ◽  
Wei-Hua Le
Keyword(s):  
Purkinje Cells ◽  
Motor Performance ◽  
Motor Coordination ◽  
Dendritic Tree ◽  
Cerebellar Nuclei ◽  
Wild Type ◽  
Cell Degeneration ◽  
Gene Effects ◽  
Neuron Populations ◽  
Behavioral Paradigm

We have previously applied neural grafting to “Purkinje cell degeneration” mutant mice (gene symbol pcd, mouse chromosome 13), a model of recessively inherited cerebello-olivary atrophy, to create appropriate interactions between wild-type and mutant cells in elucidating gene effects on the involved neuron populations and to address issues of the structural integration of donor Purkinje cells into the disrupted cerebellar loop. Behaviorally, pcd homozygotes manifest ataxic signs beginning at 3-4 wk of age. The functional effects of cerebellar transplants on motor performance have long remained an open question. The aim of the present study was to determine the recovery of motor responses in pcd mutants in a battery of behavioral tasks after bilateral transplantation of cerebellar cell suspensions (prepared from wild-type mice) into the parenchyma of the deep cerebellar nuclei of the hosts, according to a protocol that emphasizes the reconstruction of the missing inhibitory cortico-nuclear projection. With this approach, the denervated deep nuclei of the host receive a new Purkinje axonal innervation; further, most transplanted Purkinje cells end up occupying cortical localities anyway and display a correct dendritic tree orientation toward the pia. Motor coordination and fatigue resistance were assessed in a rotarod treadmill apparatus, a behavioral paradigm useful in studying various brain abiotrophies and treatments, including developmental perturbations of the cerebellar cytoarchitecture. Locomotor activity was quantified by the number of squares mice crossed as they moved about in an open-field matrix. Grafted pcd mice performed significantly better than sham-operated mutants in both of these tasks. Moreover, graft-recipient mice were able to sustain their abdomen above the floor on their limbs during movement, contrasting to the typical lowered, widened stance of sham-operated pcd mutants. These findings clearly demonstrate that bilateral transplants of fetal Purkinje cells have functional effects on motor performance in the pcd model of hereditary cerebellar ataxia.

scholarly journals Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

2019 ◽  
Vol 21 (1) ◽  
pp. 216 ◽  
Author(s):  
Francesca Prestori ◽  
Francesco Moccia ◽  
Egidio D’Angelo
Keyword(s):  
Animal Models ◽  
Purkinje Cell ◽  
Calcium Signaling ◽  
Purkinje Cells ◽  
Motor Coordination ◽  
Cerebellar Atrophy ◽  
Cerebellar Nuclei ◽  
Spinocerebellar Ataxias ◽  
Cell Degeneration ◽  
Cerebellar Purkinje Cells

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

EMG analysis of harmaline-induced tremor in normal and three strains of mutant mice with Purkinje cell degeneration and the role of the inferior olive

1995 ◽  
Vol 73 (6) ◽  
pp. 2568-2577 ◽  
Author(s):  
T. E. Milner ◽  
G. Cadoret ◽  
L. Lessard ◽  
A. M. Smith
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Mutant Mice ◽  
Posterior Lobe ◽  
Wild Type ◽  
Cell Degeneration ◽  
Purkinje Cell Degeneration ◽  
Cerebellar Mutant ◽  
Normal Wild Type

1. The effects of intraperitoneal injections of 10 mg/kg harmaline were tested in normal mice and three strains of cerebellar mutant mice with Purkinje cell degeneration. Ten normal (wild-type) mice (+/+), as well as five lurcher (lc/+), six nervous (nr/nr), and eight Purkinje cell degeneration (pcd/pcd) mutants were implanted with chronic electromyogram (EMG) electrodes in the hamstring and quadriceps muscle groups of the right hindlimb. 2. EMGs were recorded in each of the mice during spontaneous activity before and after intraperitoneal injections of 0.3 ml harmaline (10 mg/kg). Spectral analysis was used to quantify the amplitude and frequency of tremor found in the EMGs after harmaline administration. Normal mice responded to harmaline with strong, continuous 11- to 14-Hz tremor. Mutants from the pcd/pcd strain also reacted with continuous tremor, but of lower amplitude and frequency. In contrast, nr/nr mutants exhibited intermittent paroxysmal tremor lasting for only a few seconds, and lc/+ mutants showed no evidence of tremor whatsoever. 3. In order to detect covert tremor that was possibly not revealed by focal intramuscular EMG recordings, several mutant and normal mice were also tested on a suspended platform to which an accelerometer was attached. The results confirmed the findings from EMG recordings. 4. An incidental observation made during the course of this study was that harmaline tremor disappeared from the normal mouse during swimming and reappeared when the animal was withdrawn from the water. 5. Although Purkinje cells appeared to increase both the depth of modulation and the frequency of tremor, the inhibitory action of the cerebellar cortex does not seem to be essential for the generation of tremor. 6. Parasagittal cerebellar sections of the normal, wild-type mice and the three strains of cerebellar mutant mice of various ages were stained with cresyl violet and examined for Purkinje cell degeneration. Purkinje cell degeneration was found to be complete in the pcd/pcd and lc/+ strains. Although an initial examination of parasagittal sections of the nr/nr strain failed to find any surviving Purkinje cells, further examination of sections cut in the coronal plane revealed small clusters of Purkinje cells in the vermal area of the posterior lobe. 7. The retrograde transport of wheat-germ-agglutinin-conjugated horseradish peroxidase (WGA-HRP) pressure-injected into the cerebellar cortex was used to study the olivocerebellar projections in the wild-type mice and the three strains of cerebellar mutant mice.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation

2008 ◽  
Vol 295 (4) ◽  
pp. R1109-R1114 ◽  
Author(s):  
C. P. Krzyszton ◽  
N. L. Sparkman ◽  
R. W. Grant ◽  
J. B. Buchanan ◽  
S. R. Broussard ◽  
...  
Keyword(s):  
Motor Performance ◽  
Motor Coordination ◽  
Interleukin 10 ◽  
Motor Deficits ◽  
Wild Type ◽  
Age Related ◽  
Anti Inflammatory ◽  
Deficient Mice ◽  
Anti Inflammatory Cytokine ◽  
Lps Treatment

The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10+/+) and IL-10-deficient (IL-10−/−) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1β, IL-6, and TNFα mRNA in all brain areas examined in IL-10+/+and IL-10−/−mice, but to a greater extent and for a longer time in IL-10−/−mice. Plasma IL-1β and IL-6 were increased similarly in IL-10+/+and IL-10−/−mice 4 h after LPS but remained elevated longer in IL-10−/−mice, whereas TNFα was higher in IL-10−/−mice throughout after LPS treatment. Motor performance and motor learning in IL-10+/+mice were not affected by LPS treatment; however, both were reduced in IL-10−/−mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in IL-10+/+and IL-10−/−mice, the effects were exacerbated in IL-10−/−mice. Thus the increased brain and peripheral inflammation induced by LPS in IL-10−/−mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.

scholarly journals Modulatory Effects of Monoamines and Perineuronal Nets on Output of Cerebellar Purkinje Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Moritoshi Hirono ◽  
Fuyuki Karube ◽  
Yuchio Yanagawa
Keyword(s):  
Purkinje Cells ◽  
Motor Coordination ◽  
Gaba Release ◽  
Cerebellar Nuclei ◽  
Brain Regions ◽  
Perineuronal Nets ◽  
Gabaergic Transmission ◽  
Neural Connections ◽  
Brain Functions ◽  
Cerebellar Purkinje Cells

Classically, the cerebellum has been thought to play a significant role in motor coordination. However, a growing body of evidence for novel neural connections between the cerebellum and various brain regions indicates that the cerebellum also contributes to other brain functions implicated in reward, language, and social behavior. Cerebellar Purkinje cells (PCs) make inhibitory GABAergic synapses with their target neurons: other PCs and Lugaro/globular cells via PC axon collaterals, and neurons in the deep cerebellar nuclei (DCN) via PC primary axons. PC-Lugaro/globular cell connections form a cerebellar cortical microcircuit, which is driven by serotonin and noradrenaline. PCs’ primary outputs control not only firing but also synaptic plasticity of DCN neurons following the integration of excitatory and inhibitory inputs in the cerebellar cortex. Thus, strong PC-mediated inhibition is involved in cerebellar functions as a key regulator of cerebellar neural networks. In this review, we focus on physiological characteristics of GABAergic transmission from PCs. First, we introduce monoaminergic modulation of GABAergic transmission at synapses of PC-Lugaro/globular cell as well as PC-large glutamatergic DCN neuron, and a Lugaro/globular cell-incorporated microcircuit. Second, we review the physiological roles of perineuronal nets (PNNs), which are organized components of the extracellular matrix and enwrap the cell bodies and proximal processes, in GABA release from PCs to large glutamatergic DCN neurons and in cerebellar motor learning. Recent evidence suggests that alterations in PNN density in the DCN can regulate cerebellar functions.

scholarly journals Enhanced Survival of Wild-Type and Lurcher Purkinje Cells In Vitro Following Inhibition of Conventional PKCs or Stress-Activated MAP Kinase Pathways

2012 ◽  
Vol 12 (3) ◽  
pp. 377-389 ◽  
Author(s):  
Hadi S. Zanjani ◽  
Ann M. Lohof ◽  
Rebecca McFarland ◽  
Michael W. Vogel ◽  
Jean Mariani
Keyword(s):  
Map Kinase ◽  
Purkinje Cells ◽  
Wild Type ◽  
Map Kinase Pathways

scholarly journals Activation of MAP3K DLK and LZK in Purkinje Cells Causes Rapid and Slow Degeneration Depending on Signaling Strength

2020 ◽  
Author(s):  
Yunbo Li ◽  
Erin M Ritchie ◽  
Christopher L. Steinke ◽  
Cai Qi ◽  
Lizhen Chen ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Leucine Zipper ◽  
Activity Levels ◽  
Cell Type ◽  
Cell Degeneration ◽  
Mechanistic Basis ◽  
Cerebellar Purkinje Cells ◽  
Jnk Activation

SummaryThe conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Mkk7, strongly attenuates Purkinje cell degeneration induced by activation of LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

scholarly journals Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Antoine M Valera ◽  
Francesca Binda ◽  
Sophie A Pawlowski ◽  
Jean-Luc Dupont ◽  
Jean-François Casella ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Granule Cell ◽  
Motor Coordination ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
Synaptic Organization ◽  
Cerebellar Modules ◽  
Activity Dependent

Motor coordination is supported by an array of highly organized heterogeneous modules in the cerebellum. How incoming sensorimotor information is channeled and communicated between these anatomical modules is still poorly understood. In this study, we used transgenic mice expressing GFP in specific subsets of Purkinje cells that allowed us to target a given set of cerebellar modules. Combining in vitro recordings and photostimulation, we identified stereotyped patterns of functional synaptic organization between the granule cell layer and its main targets, the Purkinje cells, Golgi cells and molecular layer interneurons. Each type of connection displayed position-specific patterns of granule cell synaptic inputs that do not strictly match with anatomical boundaries but connect distant cortical modules. Although these patterns can be adjusted by activity-dependent processes, they were found to be consistent and predictable between animals. Our results highlight the operational rules underlying communication between modules in the cerebellar cortex.

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