Department of Developmental Biology, Department of Psychiatry, The Taylor Family Institute for Innovative Psychiatric Research, Department of Ophthalmology, and Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 2014 Apr 23;34(17):5800-15. doi: 10.1523/JNEUROSCI.4730-13.2014.
Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt(-/-) mice). CaMKIIαNampt(-/-) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2-3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation.
烟酰胺腺嘌呤二核苷酸 (NAD(+)) 是许多重要生物途径中的酶辅因子或共底物。迄今为止，神经元 NAD(+) 的主要来源尚不清楚。NAD(+) 可以由几种不同的前体合成，其中烟酰胺是哺乳动物中主要使用的底物。NAD(+) 生物合成途径中从烟酰胺开始的限速步骤由烟酰胺磷酸核糖基转移酶 (Nampt) 完成。在这里，我们通过生成和评估缺乏大脑前兴奋性神经元中 Nampt 的小鼠（CaMKIIαNampt(-/-) 小鼠）来检验神经元是否通过细胞内 Nampt 介导的 NAD(+) 生物合成来利用 NAD(+) 的假设。CaMKIIαNampt(-/-) 小鼠在 2-3 个月大时表现出海马和皮质萎缩、星形胶质细胞增生、小胶质细胞增生和 CA1 树突形态异常。重要的是，这些组织学变化伴随着海马内连接的改变和异常行为；包括多动、运动技能缺陷、记忆障碍和焦虑减少，但没有感觉过程受损或 Schaffer 侧支通路的长时程增强。这些结果清楚地表明，大脑前兴奋性神经元主要利用细胞内 Nampt 介导的 NAD(+) 生物合成来介导其存活和功能。研究这些神经元中特定的 NAD(+) 生物合成途径为它们对病理生理刺激的易感性以及为保护它们而开发治疗和预防干预措施提供了关键的见解。
