Murchison David, Griffith William H
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University System Health Science Center, College Station, TX 77843-1114, USA.
Aging Cell. 2007 Jun;6(3):297-305. doi: 10.1111/j.1474-9726.2007.00293.x.
Disturbances of neuronal Ca2+ homeostasis are considered to be important determinants of age-related cognitive impairment. Cholinergic neurons of the basal forebrain (BF) are principal targets of decline associated with aging and dementia. During the last several years, we have attempted to link these concepts in a rat model of 'normal' aging. In this review, we will describe some changes that we have observed in Ca2+ signaling of aged BF neurons and the reversal of one of these changes by dietary caloric restriction. Our evidence supports a scenario in which subtle changes in the properties of voltage-gated Ca2+ channels result in increased Ca2+ influx during aging. This increased Ca2+, in turn, triggers an increase in rapid Ca2+ buffering in the somatic compartment of aged BF neurons. However, this nominal 'compensation', along with other changes in Ca2+ handling machinery (notably mitochondria) alters the Ca2+ signal with age in a way that is dependent on the magnitude of the Ca2+ load. By combining whole-cell patch clamp electrophysiology, ratiometric Ca2+-sensitive microfluorimetry and single-cell reverse transcription-polymerase chain reaction, we have determined that age-related rapid buffering changes are present in identified cholinergic BF neurons and that these changes can be prevented by a caloric restriction dietary regimen. Because caloric restriction extends lifespan and retards the progression of age-related dysfunction, these findings suggest that increased Ca2+ buffering in cholinergic neurons may be relevant to cognitive decline during normal aging. Importantly, calcium homeostatic mechanisms of BF cholinergic neurons are amenable to dietary interventions that could promote cognitive health during aging.
神经元钙稳态的紊乱被认为是与年龄相关的认知障碍的重要决定因素。基底前脑（BF）的胆碱能神经元是与衰老和痴呆相关衰退的主要靶点。在过去几年中，我们试图在“正常”衰老的大鼠模型中将这些概念联系起来。在这篇综述中，我们将描述我们在老年BF神经元的钙信号中观察到的一些变化，以及饮食热量限制对其中一种变化的逆转作用。我们的证据支持这样一种情况，即电压门控钙通道特性的细微变化导致衰老过程中钙内流增加。这种增加的钙反过来又触发了老年BF神经元胞体区快速钙缓冲的增加。然而，这种名义上的“补偿”，连同钙处理机制（特别是线粒体）的其他变化，随着年龄的增长以一种依赖于钙负荷大小的方式改变了钙信号。通过结合全细胞膜片钳电生理学、比率型钙敏感微荧光测定法和单细胞逆转录聚合酶链反应，我们确定在已鉴定的胆碱能BF神经元中存在与年龄相关的快速缓冲变化，并且这些变化可以通过热量限制饮食方案来预防。由于热量限制延长了寿命并延缓了与年龄相关的功能障碍的进展，这些发现表明胆碱能神经元中钙缓冲的增加可能与正常衰老过程中的认知衰退有关。重要的是，BF胆碱能神经元的钙稳态机制适合于饮食干预，这可能在衰老过程中促进认知健康。
