Altered neuronal nitric oxide synthase expression in the cerebellum of calcium channel mutant mice

Rhyu, Im Joo; Nahm, Sang-Soep; Hwang, Seung Jun; Kim, H.; Suh, Young Suk; Oda, Sen Ichi; Frank, Tamy C; Abbott, Louise C.

doi:10.1016/s0006-8993(03)02403-x

Cited by 20 publications

(7 citation statements)

References 65 publications

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“…Such secondary effects would ultimately disrupt the normal balance of inputs to the Purkinje cell. Reduced P/Q channel conductivity may also trigger alterations in mechanisms of intracellular calcium homeostasis and thereby alter processes in which calcium acts as a second messenger, such as long-term depression or nitric oxide generation (Cicale et al 2002;Dove et al 2000;Murchison et al 2002;Rhyu et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Stahl¹,

James²,

Oommen³

et al. 2006

Journal of Neurophysiology

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Mice carrying mutations of the gene encoding the ion pore of the P/Q calcium channel (Cacna1a) are an instance in which cerebellar dysfunction may be attributable to altered electrophysiology and thus provide an opportunity to study how neuronal intrinsic properties dictate signal processing in the ocular motor system. P/Q channel mutations can engender multiple effects at the single neuron, circuit, and behavioral levels; correlating physiological and behavioral abnormalities in multiple allelic strains will ultimately facilitate determining which alterations of physiology are responsible for specific behavioral aberrations. We used videooculography to quantify ocular motor behavior in tottering mutants aged 3 mo to 2 yr and compared their performance to data previously obtained in the allelic mutant rocker and C57BL/6 controls. Tottering mutants shared numerous abnormalities with rocker, including upward deviation of the eyes at rest, increased vestibuloocular reflex (VOR) phase lead at low stimulus frequencies, reduced VOR gain at high stimulus frequencies, reduced gain of the horizontal and vertical optokinetic reflex, reduced time constants of the neural integrator, and reduced plasticity of the VOR as assessed in a cross-axis training paradigm. Unlike rocker, young tottering mutants exhibited normal peak velocities of nystagmus fast phases, arguing against a role for neuromuscular transmission defects in the attenuation of compensatory eye movements. Tottering also differed by exhibiting directional asymmetries of the gains of optokinetic reflexes. The data suggest at least four pathophysiological mechanisms (two congenital and two acquired) are required to explain the ocular motor deficits in the two Cacna1a mutant strains.

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Section: Introductionmentioning

confidence: 99%

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Stahl¹,

James²,

Oommen³

et al. 2006

Journal of Neurophysiology

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“…The three NOS isoforms have all been detected in the cerebellum (Minc-Golomb et al 1996;Rhyu et al 2003;Campese et al 2007). Yet, within the cerebellum, the role of NO in mediating the survival and morphology of cerebellar Purkinje neurons has not been previously investigated.…”

Section: Introductionmentioning

confidence: 98%

Effects of Nitric Oxide on the Survival and Neuritogenesis of Cerebellar Purkinje Neurons

2011

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Nitric oxide has been investigated widely both during neurodevelopment and in neurological diseases. However, whilst it has been established that nitric oxide-producing enzymes of nitric oxide synthase family are expressed in cerebellar Purkinje neurons, the effects of nitric oxide on the viability and morphology of these neurons remain unknown. Here, we have demonstrated that the activity of neuronal nitric oxide synthase, but not the inducible or endothelial forms of this enzyme, is required to support the survival of a proportion of cerebellar Purkinje neurons in vitro. We discovered that donation of high concentrations of exogenous nitric oxide reduces Purkinje neuron survival in culture and that peroxynitrite is also toxic to these cells. Finally, we demonstrated that exogenous nitric oxide and peroxynitrite reduce both the magnitude and the complexity of the neurite arbour extended by cerebellar Purkinje neurons. Taken together, these findings reveal that whilst a low level of endogenous nitric oxide, released by the activity of neuronal nitric oxide synthase, is beneficial to cerebellar Purkinje neurons in vitro, high levels of exogenous nitric oxide and peroxynitrite are detrimental to both the survival of these neurons and to their ability to extend processes and form functional neural networks.

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“…There are additional VDCC α 1A subunit mutants called tottering locus mutants; tottering, leaner and rocker (Zwingman et al, 2001). They show variable symptoms and pathological changes depending on their mutation points (Austin et al, 1992; Isaacs & Abbott, 1995; Rhyu et al, 1999a, 1999c; Cicale et al, 2002; Suh et al, 2002; Rhyu et al, 2003); they thus serve useful biological model for human calcium channelopathies (Rhyu et al, 1999a; Zwingman et al, 2001; Pietrobon 2002). …”

Section: Introductionmentioning

confidence: 99%

Differential regulation of Purkinje cell dendritic spines in rolling mouse Nagoya (tg^rol/tg^rol), P/Q type calcium channel (α1_A/Ca_v2.1) mutant

et al. 2010

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Voltage dependent calcium channels (VDCC) participate in regulation of neuronal Ca2+. The Rolling mouse Nagoya (Cacna1atg-rol) is a spontaneous P/Q type VDCC mutant, which has been suggested as an animal model for some human neurological diseases such as autosomal dominant cerebellar ataxia (SCA6), familial hemiplegic migraine and episodic ataxia type-2. Morphology of Purkinje cell (PC) dendritic spine is suggested to be regulated by signal molecules such as Ca2+ and by interactions with afferent inputs. The amplitude of excitatory postsynaptic current was decreased in parallel fiber (PF) to PC synapses, whereas apparently increased in climbing fiber (CF) to PC synapses in rolling mice Nagoya. We have studied synaptic morphology changes in cerebella of this mutant strain. We previously found altered synapses between PF varicosity and PC dendritic spines. To study dendritic spine plasticity of PC in the condition of insufficient P/Q type VDCC function, we used high voltage electron microscopy (HVEM). We measured the density and length of PC dendritic spines at tertiary braches. We observed statistically a significant decrease in spine density as well as shorter spine length in rolling mice compared to wild type mice at tertiary dendritic braches. In proximal PC dendrites, however, there were more numerous dendritic spines in rolling mice Nagoya. The differential regulation of rolling PC spines at tertiary and proximal dendrites in rolling mice Nagoya suggests that two major excitatory afferent systems may be regulated reciprocally in the cerebellum of rolling mouse Nagoya.

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Altered neuronal nitric oxide synthase expression in the cerebellum of calcium channel mutant mice

Cited by 20 publications

References 65 publications

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Effects of Nitric Oxide on the Survival and Neuritogenesis of Cerebellar Purkinje Neurons

Differential regulation of Purkinje cell dendritic spines in rolling mouse Nagoya (tg^rol/tg^rol), P/Q type calcium channel (α1_A/Ca_v2.1) mutant

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Altered neuronal nitric oxide synthase expression in the cerebellum of calcium channel mutant mice

Cited by 20 publications

References 65 publications

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Eye Movements of the Murine P/Q Calcium Channel Mutant Tottering, and the Impact of Aging

Effects of Nitric Oxide on the Survival and Neuritogenesis of Cerebellar Purkinje Neurons

Differential regulation of Purkinje cell dendritic spines in rolling mouse Nagoya (tgrol/tgrol), P/Q type calcium channel (α1A/Cav2.1) mutant

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Differential regulation of Purkinje cell dendritic spines in rolling mouse Nagoya (tg^rol/tg^rol), P/Q type calcium channel (α1_A/Ca_v2.1) mutant