A Role for Myosin Va in Cerebellar Plasticity and Motor Learning: A Possible Mechanism Underlying Neurological Disorder in Myosin Va Disease

Miyata, Mariko; Kishimoto, Yasushi; Tanaka, Masahiko; Hashimoto, Kouichi; Hirashima, Naohide; Murata, Yoshiharu; Kano, Masanobu; Takagishi, Yoshiko

doi:10.1523/jneurosci.5651-10.2011

Cited by 32 publications

(30 citation statements)

References 60 publications

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“…Consequently, the timing of CRs was the same as in physiological conditions (Fig. 8C), as demonstrated also by experimental data 25 : for both onset and peak latencies, the Wilcoxon-Mann-Whitney test proved that healthy and pathological values were comparable, with p=0.98 and p=0.20, respectively.…”

Section: Impaired Ltd At Pf-pc Synapsessupporting

confidence: 76%

“…The evolution of %CR agreed with the results obtained during the multi-session protocol in the reference study. 25 The analysis of weights showed that for all the plasticity sites, the pathological values moved in the same direction as normal values, but the initial differences highlighted in the first session affected even the long protocol (Fig. 9C). …”

Section: Impaired Ltd At Pf-pc Synapsesmentioning

confidence: 82%

“…[53][54][55] The reference study analysed adaptation during an EBCC task in mice reporting damaged LTD at PF-PC synapses. 25 In particular, LTD impairment at this plasticity site resulted from the mutation of the gene encoding Myosin Va, which is also the cause of neurological diseases like Griscelli syndrome type1 and Elejalde syndrome in humans. In our cerebellar network, the same alteration was reproduced by decreasing the parameter 1 that regulated LTD at the PF-PC plasticity site.…”

Section: Impaired Ltd At Pf-pc Synapsesmentioning

confidence: 99%

“…In such condition, the model was able to reproduce impaired associative learning in mice. 25 CR acquisition was delayed and reduced to a degree depending on the amount of LTD reduction. However, even in case of severe damage, CR acquisition could be at least partially restored over a prolonged acquisition session.…”

Section: Impaired Ltd At Pf-pc Synapsesmentioning

confidence: 99%

“…24 The last case reproduced an impairment of long-term depression, the main mechanism of supervised cerebellar cortical plasticity. 25 After tuning model parameters to simulate the standard physiological conditions, appropriate alterations were introduced in order to reproduce the pathological changes observed in humans or animals and, in these pathological cases, the EBCC was simulated and analyzed.…”

Section: Introductionmentioning

confidence: 99%

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A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies

Geminiani

Casellato

Antonietti

et al. 2018

Int. J. Neur. Syst.

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The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyse the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies.

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Section: Impaired Ltd At Pf-pc Synapsessupporting

confidence: 76%

Section: Impaired Ltd At Pf-pc Synapsesmentioning

confidence: 82%

Section: Impaired Ltd At Pf-pc Synapsesmentioning

confidence: 99%

Section: Impaired Ltd At Pf-pc Synapsesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies

Geminiani

Casellato

Antonietti

et al. 2018

Int. J. Neur. Syst.

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Dendritic differentiation of cerebellar Purkinje cells is promoted by ryanodine receptors expressed by Purkinje and granule cells

Ohashi

Sakata

Naito

et al. 2013

Developmental Neurobiology

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Cerebellar Purkinje cells have the most elaborate dendritic trees among neurons in the brain. We examined the roles of ryanodine receptor (RyR), an intracellular Ca(2+) release channel, in the dendrite formation of Purkinje cells using cerebellar cell cultures. In the cerebellum, Purkinje cells express RyR1 and RyR2, whereas granule cells express RyR2. When ryanodine (10 µM), a blocker of RyR, was added to the culture medium, the elongation and branching of Purkinje cell dendrites were markedly inhibited. When we transferred small interfering RNA (siRNA) against RyR1 into Purkinje cells using single-cell electroporation, dendritic branching but not elongation of the electroporated Purkinje cells was inhibited. On the other hand, transfection of RyR2 siRNA into granule cells also inhibited dendritic branching of Purkinje cells. Furthermore, ryanodine reduced the levels of brain-derived neurotrophic factor (BDNF) in the culture medium. The ryanodine-induced inhibition of dendritic differentiation was partially rescued when BDNF was exogenously added to the culture medium in addition to ryanodine. Overall, these results suggest that RyRs expressed by both Purkinje and granule cells play important roles in promoting the dendritic differentiation of Purkinje cells and that RyR2 expressed by granule cells is involved in the secretion of BDNF from granule cells.

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Optimization of Single-Cell Electroporation Protocol for Forced Gene Expression in Primary Neuronal Cultures

2014

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The development and function of the central nervous system (CNS) are realized through interactions between many neurons. To investigate cellular and molecular mechanisms of the development and function of the CNS, it is thus crucial to be able to manipulate the gene expression of single neurons in a complex cell population. We recently developed a technique for gene silencing by introducing small interfering RNA into single neurons in primary CNS cultures using single-cell electroporation. However, we had not succeeded in forced gene expression by introducing expression plasmids using single-cell electroporation. In the present study, we optimized the experimental conditions to enable the forced expression of green fluorescent protein (GFP) in cultured cerebellar Purkinje neurons using single-cell electroporation. We succeeded in strong GFP expression in Purkinje neurons by increasing the inside diameter of micropipettes or by making the size of the original plasmid smaller by digestion and cyclizing it by ligation. Strong GFP expression in Purkinje neurons electroporated under the optimal conditions continued to be observed for more than 25 days after electroporation. Thus, this technique could be used for forced gene expression in single neurons to investigate cellular and molecular mechanisms of the development, function, and disease of the CNS.

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A Role for Myosin Va in Cerebellar Plasticity and Motor Learning: A Possible Mechanism Underlying Neurological Disorder in Myosin Va Disease

Cited by 32 publications

References 60 publications

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies

Dendritic differentiation of cerebellar Purkinje cells is promoted by ryanodine receptors expressed by Purkinje and granule cells

Optimization of Single-Cell Electroporation Protocol for Forced Gene Expression in Primary Neuronal Cultures

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