Booker Sam A, Campbell Graham R, Mysiak Karolina S, Brophy Peter J, Kind Peter C, Mahad Don J, Wyllie David J A
Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
J Physiol. 2017 Mar 15;595(6):2147-2160. doi: 10.1113/JP273581.
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.
神经退行性疾病可表现出线粒体呼吸链复合体IV活性功能失调。在小鼠海马齿状颗粒细胞中条件性缺失细胞色素c氧化酶（线粒体呼吸电子传递链中的末端酶），并不影响低频下齿状回至CA3区的谷氨酸能突触传递。在细胞色素c氧化酶缺陷型小鼠中，高频下齿状回至CA3区的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至CA3突触功能的短期动态变化至关重要。
神经退行性疾病的特征是外周和中枢症状，包括认知障碍，这些症状与线粒体功能降低有关，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，我们在成年齿状回的颗粒细胞中条件性去除了复合体IV的一个关键成分，即由COX10基因编码的原卟啉IX法尼基转移酶。利用对来自对照小鼠和复合体IV缺陷型小鼠的形态学鉴定的CA3锥体细胞进行全细胞膜片钳记录，我们发现线粒体功能降低并未导致苔藓纤维突触处基础谷氨酸能突触传递出现明显缺陷，因为从齿状颗粒细胞中去除COX10后，突触后电位的幅度、输入-输出关系和50毫秒配对脉冲易化均未改变。然而，高频（>20Hz）刺激序列导致短期易化显著降低，在最高频率（>50Hz）时，配对脉冲易化也降低，这表明需要足够的线粒体功能来在生理相关的活动模式期间维持谷氨酸释放。有趣的是，局部抑制降低，这表明观察到的效应并不局限于通过大型苔藓纤维终扣与CA3锥体细胞形成的突触，而是涉及齿状颗粒细胞形成的所有突触。因此，突触前线粒体功能对于突触功能的短期动态变化至关重要，这可能导致在病理性线粒体功能障碍中观察到的认知缺陷。
