Atm-deficient mice Purkinje cells show age-dependent defects in calcium spike bursts and calcium currents
Section snippets
Experimental procedures
All experiments conformed to local and international guidelines on the ethical use of animals, and all efforts were made to minimize the number of animals used and their suffering.
Morphological analysis
The Atm-deficient mice cerebella displayed a normal morphology with a typical foliation pattern and cortical layering, as described previously at a qualitative level.3 We made a quantitative evaluation of the cortical thickness in randomly selected samples of molecular and granular layers. For the molecular layer, the analysis was performed on five wild-type and five Atm-deficient mice, and for the granular layer on two wild-type and two Atm-deficient mice. All animals were eight to 12 weeks
Discussion
Atm-deficient mice display many of the features of AT and are an animal model of the human disease. Among the numerous alterations of this human disease, there is ataxia with widespread neuronal degeneration, especially in the nerve cells of the cerebellar cortex.41 In contrast, Atm-deficient mice present abnormalities in motor behaviour3 and a grossly normal cerebellar structure without neurodegeneration.3., 16., 18., 46. The reasons for the different patterns of the disease are unknown, but
Acknowledgements
We thank Dr Annalisa Buffo for help with immunohistochemical procedures and Mrs Luisella Milano for technical help. We also thank Dr Emilio Carbone and Dr Chris McBain for critically reviewing the manuscript. This work was supported by a grant from the AT Children's Project to P. Strata and by grant no. ICS120.3/RF98.83 of the Italian Health Ministry.
References (47)
- et al.
Oxidative stress affects the selective ion permeability of voltage-sensitive Ca2+ channels in cultured retinal cells
Neurosci. Res.
(1997) - et al.
Atm-deficient mice: a paradigm of ataxia telangiectasia
Cell
(1996) - et al.
Multiple ATM-dependent pathways: an explanation for pleiotropy
Am. J. hum. Genet.
(1999) Calbindin D-28k and parvalbumin in the rat nervous system
Neuroscience
(1990)Glutamate neurotoxicity and diseases of the nervous system
Neuron
(1988)- et al.
An experimental model for the non-invasive trans-synaptic induction of nitric oxide synthase in Purkinje cells of the rat cerebellum
Neuroscience
(1996) - et al.
Initiation and spread of sodium action potentials in cerebellar Purkinje cells
Neuron
(1994) - et al.
Enhanced phosphorylation of p53 by ATM in response to DNA damage
Science
(1998) - et al.
Loss of the ataxia–telangiectasia gene product causes oxidative damage in target organs
Proc. natn. Acad. Sci. U.S.A.
(1999) - et al.
ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation
Proc. natn. Acad. Sci. U.S.A.
(2000)
Ataxia–telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation
Nature
Activation of the ATM kinase by ionizing radiation and phosphorylation of p53
Science
Prediction of repetitive firing behavior from voltage clamp data on an isolated neuron soma
J. Physiol., Lond.
Inward rectification and low threshold calcium conductance in rat cerebellar Purkinje cells. An in vitro study
J. Physiol., Lond.
Whole cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice
J. Neurosci.
A thin slice preparation for patch clamp recordings from neurons of the mammalian central nervous system
Pflügers Arch.
Pleiotropic defects in ataxia-telangiectasia protein-deficient mice
Proc. natn. Acad. Sci. U.S.A.
Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system
Science
Modulation of ion-channel function by G-protein-coupled receptors
Trends Neurosci.
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons
Nature
Cited by (46)
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype
2018, DNA RepairCitation Excerpt :Atm-deficient mice were found to recapitulate major A-T symptoms, including the profound cancer predisposition, acute radiation sensitivity and sterility, but were largely spared the progressive cerebellar atrophy [51–54]. Several studies noted, however, morphological and functional abnormalities in the cerebellar cortex of Atm-deficient mice, such as ectopic and abnormally differentiated Purkinje cells [54], decreased duration of calcium currents and firing in these cells [55], and degenerative changes in several types of neurons, identified using electron microscopy [56]. Further abnormalities were observed in tissue organization and various physiological and molecular circuits of the murine Atm-deficient nervous system [39,51–70].
Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome
2017, Redox BiologyCitation Excerpt :Ward et al. [34] claim that the genotype of A-T cells affects their response to DNA damaging sources through inflammatory processes, which can also be regarded as a major source of oxidative stress. Neurodegeneration and cancer susceptibility are the most debilitating manifestations of A-T disease and a major cause of death in A-T patients [37]. Kamsler et al. [38] and Barlow et al. [39] demonstrated ROS overproduction in brain tissue of Atm-deficient mice.
Genome instability: Linking ageing and brain degeneration
2017, Mechanisms of Ageing and DevelopmentCitation Excerpt :These studies are usually based on the mouse model of A-T—the Atm-knockout mouse, which recapitulates most A-T symptoms with the exception of the severe progressive brain degeneration (Barlow et al., 1996; Borghesani et al., 2000; Elson et al., 1996; Xu et al., 1996). Minor neurological abnormalities including decrease in electrophysiological activity of neurons were, however, noticed in these animals (Borghesani et al., 2000; Chiesa et al., 2000; Kuljis et al., 1997), suggesting that, if given enough time, a distinct neurological phenotype might develop in the animals (in human A-T patients the cerebellar atrophy culminates at 8–10 years of age). Importantly, the phenotypic similarity between A-T, AOA1, AOA2 and SCAN1 is reflected in the corresponding mouse models, which were generated by knocking out the corresponding murine genes (Atm, Aptx, Setx and Tdp1, respectively): in all of them, the sensitivity to specific DNA damaging agents is recapitulated by the animal, but not the human cerebellar degeneration (Becherel et al., 2013; El-Khamisy et al., 2009; Gomez-Herreros et al., 2013, 2014).
Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders
2016, Genomics, Proteomics and BioinformaticsCitation Excerpt :Thus, an additional implication of the study by Levine-Small et al. is that understanding the systems-level network is critically important for general comprehension of BDDs and for the development of treatment modalities for brain illness. In a quest to understand the role of ATM in the activity of Purkinje cells, Chiesa et al. conducted morphological and electrophysiological analyses of Purkinje cells from ATM−/− mice of different ages [41]. No histological or immunohistochemical abnormalities were found in these mice.
Motor pathway degeneration in young ataxia telangiectasia patients: A diffusion tractography study
2015, NeuroImage: Clinical
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Present address: The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA 92037, U.S.A.
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Present address: University of California, San Diego School of Medicine, La Jolla, CA 92093-0627, U.S.A.
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Present address: Institute of Human Physiology, University of Perugia, Perugia 06126, Italy.