Losing the Beat: Contribution of Purkinje Cell Firing Dysfunction to Disease, and Its Reversal

Cook, Anna A.; Fields, Eviatar; Watt, Alanna J.

doi:10.1016/j.neuroscience.2020.06.008

Cited by 56 publications

(73 citation statements)

References 129 publications

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“…Our observation that Atm R35X/R35X ; Aptx -/- mice display differences in cerebellar physiology, specifically decreased spontaneous PN action potential firing frequency, changes in morphology, and ultimately PN death is in line with multiple other ataxic mouse model studies, including those focused on spinocerebellar ataxias (SCA) 1, 2, 3, 5, 6, and 13 (see review (Cook, Fields, and Watt 2020)). In Atm R35X/R35X ; Aptx -/- mice, we find that reduced PN firing frequency and morphological size is correlated with only mild behavioral deficits.…”

Section: Discussionsupporting

confidence: 63%

“…Ataxia in A-T is thought to result from cerebellar dysfunction; however, the progression and underlying mechanism is unclear. Decreased spontaneous action potential firing rates in cerebellar Purkinje neurons (PN) has been linked to several forms of heritable ataxia (Cook, Fields, and Watt 2020). We therefore sought to determine if PN action potential firing rates in Atm R35X/R35X ; Aptx -/- are abnormally low compared to control mice.…”

Section: Resultsmentioning

confidence: 99%

“…S3 ). Previous studies in mouse models of heritable ataxia indicate that physiological disruption in PN firing not only includes changes in frequency but also affects its regularity (Cook, Fields, and Watt 2020). We compared both the coefficient of variation (CV) and variability in adjacent intervals (CV2) between Atm R35X/R35X ; Aptx -/- and control mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Atm and Aptx Deficiency Is Necessary To Disrupt Cerebellar Nmentioning

confidence: 99%

See 3 more Smart Citations

A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

Perez

Abdallah

Chavira

et al. 2020

Preprint

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Ataxia Telangiectasia (A-T) is caused by null mutations in the genome stability gene, ATM (A-T mutated). In mice, similar null mutations do not replicate A-T’s characteristic severe ataxia with associated cerebellar dysfunction and atrophy. By increasing genotoxic stress, through the insertion of null mutations in the Atm (nonsense) and related Aptx (knockout) genes, we have generated a novel A-T mouse that first develops mild ataxia, associated with abnormal Purkinje neuron (PN) activity and decreased size, progressing to severe ataxia correlated with further reduced PN activity as well as PN loss and overall cerebellar atrophy. These mice also exhibit high incidences of cancer and immune abnormalities that are all hallmarks of the human disorder. Enabled by the insertion of a clinically relevant nonsense mutation in Atm, we demonstrate that small molecule readthrough (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Atm and Aptx Deficiency Is Necessary To Disrupt Cerebellar Nmentioning

confidence: 99%

See 2 more Smart Citations

A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

Perez

Abdallah

Chavira

et al. 2020

Preprint

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“…We found that chronic voluntary exercise partially restored cerebellar BDNF levels, as well as rescuing motor coordination deficits. Interestingly, Purkinje cell firing deficits, which we have previously reported in SCA6 84Q/84Q mice 21 , were also reversed, suggesting that Purkinje cell firing deficits can be used as a read-out of cerebellar function in ataxia 22 . To test whether cerebellar BDNF signaling mediated the effects of exercise on ataxia in SCA6, we used a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) to mimic BDNF signaling.…”

Section: Introductionsupporting

confidence: 60%

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Cook

Jayabal

Sheng

et al. 2021

Preprint

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Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in several neurodegenerative diseases, including in post-mortem tissue from SCA6 patients. Here, we show that cerebellar BDNF levels are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of voluntary exercise was sufficient to elevate BDNF expression, as well as rescue both motor coordination and cerebellar Purkinje cell firing rate deficits. A BDNF mimetic, 7,8- dihydroxyflavone (7,8-DHF) likewise improved motor coordination and reversed Purkinje cell firing rate deficits, suggesting that exercise acts via BDNF-TrkB signaling. Prolonged chronic 7,8-DHF administration rescued ataxia when treatment commenced near disease onset, but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.

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Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism‐like neurobehavioral phenotype in a rat model

et al. 2022

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The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/À) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18 m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/À rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/À rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. Lay SummaryThis study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders.

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Losing the Beat: Contribution of Purkinje Cell Firing Dysfunction to Disease, and Its Reversal

Cited by 56 publications

References 129 publications

A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism‐like neurobehavioral phenotype in a rat model

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