Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.
Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.
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DOI：
10.1113/jp273581
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发表时间：
2017-03-15
期刊：
影响因子：
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通讯作者：
Wyllie DJ
中科院分区：
文献类型：
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作者：
Booker SA;Campbell GR;Mysiak KS;Brophy PJ;Kind PC;Mahad DJ;Wyllie DJ
神经退行性疾病可表现出线粒体呼吸链复合体IV活性异常。小鼠海马齿状颗粒细胞条件性缺失细胞色素c氧化酶（线粒体呼吸电子传递链的末端酶）不影响低频齿状到CA3谷氨酸突触传递。细胞色素c氧化酶缺乏小鼠的高频齿状向CA3谷氨酸能突触传递和前馈抑制显著减弱。完整的突触前线粒体功能对于苔藓纤维对CA3突触功能的短期动态至关重要。神经退行性疾病的特点是外周和中枢症状，包括与线粒体功能降低有关的认知障碍，特别是线粒体呼吸链复合体IV或细胞色素c氧化酶活性降低。在本研究中，我们有条件地去除成人齿状回颗粒细胞中复合体IV的一个关键成分，即由COX10基因编码的原血红素IX法尼基转移酶。利用来自对照小鼠和复合体IV缺陷小鼠的形态学鉴定的CA3锥体细胞的全细胞膜片钳记录，我们发现线粒体功能的降低并没有导致苔藓纤维突触基础谷氨酸突触传递的明显缺陷，因为从齿状颗粒细胞中去除COX10后，振幅、输入输出关系和50 ms配对脉冲易化没有改变。然而，高频刺激（> - 20hz）导致短期促进作用显著降低，在最高频率（> - 50hz）下，配对脉冲促进作用也降低，这表明在生理相关活动模式下，需要足够的线粒体功能来维持谷氨酸释放。有趣的是，局部抑制减弱，这表明观察到的影响并不局限于CA3锥体细胞通过大苔藓纤维钮扣形成的突触，而是所有由齿状颗粒细胞形成的突触。因此，突触前线粒体功能对突触功能的短期动态至关重要，这可能导致病理性线粒体功能障碍中观察到的认知缺陷。神经退行性疾病可表现出线粒体呼吸链复合体IV活性异常。小鼠海马齿状颗粒细胞条件性缺失细胞色素c氧化酶（线粒体呼吸电子传递链的末端酶）不影响低频齿状到CA3谷氨酸突触传递。细胞色素c氧化酶缺乏小鼠的高频齿状向CA3谷氨酸能突触传递和前馈抑制显著减弱。完整的突触前线粒体功能对于苔藓纤维对CA3突触功能的短期动态至关重要。
Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low‐frequency dentate to CA3 glutamatergic synaptic transmission. High‐frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase‐deficient mice. Intact presynaptic mitochondrial function is critical for the short‐term dynamics of mossy fibre to CA3 synaptic function. Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole‐cell patch‐clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV‐deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy‐fibre synapse because the amplitude, input–output relationship and 50 ms paired‐pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short‐term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired‐pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses with CA3 pyramidal cells via large mossy‐fibre boutons, but rather to all synapses formed by dentate granule cells. Therefore, presynaptic mitochondrial function is critical for the short‐term dynamics of synapse function, which may contribute to the cognitive deficits observed in pathological mitochondrial dysfunction. Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low‐frequency dentate to CA3 glutamatergic synaptic transmission. High‐frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase‐deficient mice. Intact presynaptic mitochondrial function is critical for the short‐term dynamics of mossy fibre to CA3 synaptic function.