Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra, Ravi; Shakkottai, Vikram G.

doi:10.2217/fnl.14.6

Cited by 27 publications

(25 citation statements)

References 48 publications

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“…Rescue of spontaneous firing rate deficits independent of excitability deficits appears to correlate best with rescue of motor deficits, which although not a canonical deficit in ASD, is a frequent comorbid finding ( Fournier et al, 2010 ; Ming et al, 2007 ; Mosconi et al, 2015 ). Association of motor deficits with spontaneous firing deficits, independent of excitability deficits, is consistent with previous studies ( Chopra and Shakkottai, 2014 ), while rescue of this specific electrophysiological phenotype supports a possible mechanism that mTOR-related regulation of specific ion channels ( Häusser et al, 2004 ; Raman and Bean, 1997 ) at specific developmental periods may be driving these observed effects. Studies further characterizing the molecular basis for these findings will be an important avenue of future study.…”

Section: Discussionsupporting

confidence: 90%

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

et al. 2018

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SUMMARYDespite a prevalence exceeding 1%, mechanisms underlying autism spectrum disorders (ASDs) are poorly understood, and targeted therapies and guiding parameters are urgently needed. We recently demonstrated that cerebellar dysfunction is sufficient to generate autistic-like behaviors in a mouse model of tuberous sclerosis complex (TSC). Here, using the mechanistic target of rapamycin (mTOR)-specific inhibitor rapamycin, we define distinct sensitive periods for treatment of autistic-like behaviors with sensitive periods extending into adulthood for social behaviors. We identify cellular and electro-physiological parameters that may contribute to behavioral rescue, with rescue of Purkinje cell survival and excitability corresponding to social behavioral rescue. In addition, using anatomic and diffusion-based MRI, we identify structural changes in cerebellar domains implicated in ASD that correlate with sensitive periods of specific autism-like behaviors. These findings thus not only define treatment parameters into adulthood, but also support a mechanistic basis for the targeted rescue of autism-related behaviors.

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Section: Discussionsupporting

confidence: 90%

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

et al. 2018

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“…Impaired cognitive performance, involving language, executive, visuospatial and sequencing functions has also been found in patients with cerebellar atrophy [4][5], a condition characterized by diffuse degeneration of the cerebellar cortex, which is regarded as the central computational integrator of the cerebellar system [6]. Throughout the cerebellar cortex, the information ultimately converges on Purkinje neurons and is then funneled out through the neurons of the deep cerebellar nuclei (DCN), the sole output of the cerebellar cortex.…”

Section: Introductionmentioning

confidence: 99%

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2

et al. 2018

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease involving the cerebellum and characterized by a typical motor syndrome. In addition, the presence of cognitive impairment is now widely acknowledged as a feature of SCA2. Given the extensive connections between the cerebellum and associative cerebral areas, it is reasonable to hypothesize that cerebellar neurodegeneration associated with SCA2 may impact on the cerebellar modulation of the cerebral cortex, thus resulting in functional impairment. The aim of the present study was to investigate and quantitatively map the pattern of cerebellar gray matter (GM) atrophy due to SCA2 neurodegeneration and to correlate that with patients' cognitive performances. Cerebellar GM maps were extracted and compared between SCA2 patients (n = 9) and controls (n = 33) by using voxel-based morphometry. Furthermore, the relationship between cerebellar GM atrophy and neuropsychological scores of the patients was assessed. Specific cerebellar GM regions were found to be affected in patients. Additionally, GM loss in cognitive posterior lobules (VI, Crus I, Crus II, VIIB, IX) correlated with visuospatial, verbal memory and executive tasks, while additional correlations with motor anterior (V) and posterior (VIIIA, VIIIB) lobules were found for the tasks engaging motor and planning components. Our results provide evidence that the SCA2 neurodegenerative process affects the cerebellar cortex and that MRI indices of atrophy in different cerebellar subregions may account for the specificity of cognitive symptomatology observed in patients, as result of a cerebello-cerebral dysregulation.

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“…Cerebellar Purkinje neurons are able to support autonomous spiking in the absence of synaptic input, a property which depends crucially on appropriate function of a number of potassium (K + ) channels [ 8 – 10 ]. Much is known about how perturbations in K + channels affect Purkinje neuron spiking [ 11 – 13 ], including a number of studies which have identified changes in K + channels that produce aberrant spiking in mouse models of cerebellar ataxia [ 14 – 17 ]. Notably, targeting K + channels involved in aberrant spiking slows Purkinje neuron degeneration in several ataxia models [ 15 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Dendritic potassium channel dysfunction may contribute to dendrite degeneration in spinocerebellar ataxia type 1

2018

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Purkinje neuron dendritic degeneration precedes cell loss in cerebellar ataxia, but the basis for dendritic vulnerability in ataxia remains poorly understood. Recent work has suggested that potassium (K+) channel dysfunction and consequent spiking abnormalities contribute to Purkinje neuron degeneration, but little attention has been paid to how K+ channel dysfunction impacts dendritic excitability and the role this may play in the degenerative process. We examined the relationship between K+ channel dysfunction, dendritic excitability and dendritic degeneration in spinocerebellar ataxia type 1 (SCA1). Examination of published RNA sequencing data from SCA1 mice revealed reduced expression of several K+ channels that are important regulators of excitability in Purkinje neuron dendrites. Patch clamp recordings in Purkinje neurons from SCA1 mice identified increased dendritic excitability in the form of enhanced back-propagation of action potentials and an increased propensity to produce dendritic calcium spikes. Dendritic excitability could be rescued by restoring expression of large-conductance calcium-activated potassium (BK) channels and activating other K+ channels with baclofen. Importantly, this treatment combination improves motor performance and mitigates dendritic degeneration in SCA1 mice. These results suggest that reduced expression of K+ channels results in persistently increased dendritic excitability at all stages of disease in SCA1, which in turn may contribute to the dendritic degeneration that precedes cell loss.

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Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Cited by 27 publications

References 48 publications

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

Structural cerebellar correlates of cognitive functions in spinocerebellar ataxia type 2

Dendritic potassium channel dysfunction may contribute to dendrite degeneration in spinocerebellar ataxia type 1

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