Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia–telangiectasia

Neural degeneration is one of the clinical manifestations of ataxia–telangiectasia, a disorder caused by mutations in the Atm protein kinase gene. However, neural degeneration was not detected with general purpose light microscopic methods in previous studies using several different lines of mice with disrupted Atm genes. Here, we show electron microscopic evidence of degeneration of several different types of neurons in the cerebellar cortex of 2-month-old Atm knockout mice, which is accompanied by glial activation, deterioration of neuropil structure, and both pre- and postsynaptic degeneration. These findings are similar to those in patients with ataxia–telangiectasia, indicating that Atm knockout mice are a useful model to elucidate the mechanisms underlying neurodegeneration in this condition and to develop and test strategies to palliate and prevent the disease.

神经退行性变是共济失调毛细血管扩张症（ataxia–telangiectasia）的临床表现之一，该疾病由ATM蛋白激酶基因（Atm protein kinase gene）突变引发。然而，既往使用多种ATM基因敲除小鼠品系开展的相关研究中，并未通过通用光学显微镜方法检测到神经退行性变。本研究借助电子显微镜，在2月龄ATM基因敲除小鼠的小脑皮层中观察到多种神经元发生退行性变，同时伴随胶质细胞激活、神经毡（neuropil）结构受损，以及突触前与突触后退行性改变。上述研究结果与共济失调毛细血管扩张症患者的病理表现高度相似，表明ATM基因敲除小鼠是阐明此类疾病神经退行性变潜在机制、开发并测试缓解与预防该疾病策略的实用动物模型。