Billard J M
Neurobiologie de la Croissance et de la Sénescence, UMR 549 INSERM, Faculté de Médecine, Université Paris-Descartes, IFR Broca-Sainte Anne, 2 ter rue d'Alésia, 75014 Paris, France.
Magnes Res. 2006 Sep;19(3):199-215.
Ageing is associated with a general decline in physiological functions. Amongst the different aspects of body deterioration, cognitive impairments, and particularly defects in learning and memory, represent one of the most frequent features in the elderly. However, a great variability exists among aged subjects. Clinical reports and experimental data in animal models of ageing have shown that age-associated memory deficits are broadly identical to those induced by damage to the hippocampus. It is therefore not surprising that many functional properties of hippocampal neuronal networks are particularly altered with ageing. Whereas passive membrane properties of neurons are conserved with age, neuronal excitability is altered, in keeping with weaker performances of aged subjects in memory tasks. Synaptic transmission within hippocampal networks also decreases in brain ageing. Deficits concern both glutamatergic and cholinergic pathways, which represent the main excitatory neurotransmitter systems responsible for neuronal communication in the hippocampus. In addition, long-term changes in synaptic transmission, possible cellular substrates for learning and memory, are also impaired in ageing in correlation with cognitive impairments. Neuronal properties and synaptic plasticity closely depend on ion exchanges between intra- and extracellular compartments. Changes in ion regulation during ageing may therefore participate in altering functional properties of neuronal networks. Calcium dysregulation has been extensively investigated in brain ageing but the role of magnesium has received less attention though ageing constitutes a risk factor for magnesium deficit. One of general properties of magnesium at presynaptic fibre terminals is to reduce transmitter release. At the postsynaptic level, it closely controls the activation of the N-methyl-D-aspartate receptor, a subtype of glutamate receptor, which is critical for the expression of long-term changes in synaptic transmission. In addition, magnesium is a cofactor of many enzymes localized either in neurons or in glial cells that control neuronal properties and synaptic plasticity such as protein-kinase C, calcium/calmodulin-dependent protein kinase II and serine racemase. It is therefore likely that a change in magnesium concentration would significantly impair synaptic functions in the aged hippocampus. Experiments addressing this question remain too scarce but recent data indicate that magnesium is involved in age-related deficits in transmitter release, neuronal excitability and in some forms of synaptic plasticity such as long-term depression of synaptic transmission. Further studies are still necessary to better delineate to what extent magnesium contributes to the impaired cellular mechanisms of cognitive functions in the elderly which will help to develop new strategies to minimize age-related memory declines.
衰老与生理功能的普遍衰退相关。在身体机能衰退的不同方面中,认知障碍,尤其是学习和记忆缺陷,是老年人最常见的特征之一。然而,老年个体之间存在很大差异。衰老动物模型的临床报告和实验数据表明,与年龄相关的记忆缺陷与海马体损伤所致的缺陷大致相同。因此,海马体神经网络的许多功能特性会随着衰老而发生特别改变也就不足为奇了。虽然神经元的被动膜特性在衰老过程中得以保留,但神经元兴奋性发生了改变,这与老年个体在记忆任务中的较弱表现相符。海马体网络内的突触传递在脑衰老过程中也会减少。缺陷涉及谷氨酸能和胆碱能通路,这两条通路是负责海马体神经元通讯的主要兴奋性神经递质系统。此外,作为学习和记忆可能的细胞基础,突触传递的长期变化在衰老过程中也会受损,且与认知障碍相关。神经元特性和突触可塑性密切依赖于细胞内和细胞外区室之间的离子交换。因此,衰老过程中离子调节的变化可能参与改变神经网络的功能特性。钙调节异常在脑衰老过程中已得到广泛研究,但镁的作用却较少受到关注,尽管衰老构成镁缺乏的一个风险因素。镁在突触前纤维终末的一个普遍特性是减少神经递质释放。在突触后水平,它密切控制N-甲基-D-天冬氨酸受体(一种谷氨酸受体亚型)的激活,该受体对突触传递长期变化的表达至关重要。此外,镁是许多定位于神经元或胶质细胞中的酶的辅助因子,这些酶控制神经元特性和突触可塑性,如蛋白激酶C、钙/钙调蛋白依赖性蛋白激酶II和丝氨酸消旋酶。因此,镁浓度的变化很可能会显著损害老年海马体中的突触功能。针对这个问题的实验仍然太少,但最近的数据表明,镁与递质释放、神经元兴奋性以及某些形式的突触可塑性(如突触传递的长期抑制)的年龄相关缺陷有关。仍需要进一步研究以更好地确定镁在多大程度上导致老年人认知功能细胞机制受损,这将有助于制定新策略以尽量减少与年龄相关的记忆衰退。
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