Fortress Ashley M, Hamlett Eric D, Vazey Elena M, Aston-Jones Gary, Cass Wayne A, Boger Heather A, Granholm Ann-Charlotte E
Department of Neurosciences and.
Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky 40506.
J Neurosci. 2015 Jan 28;35(4):1343-53. doi: 10.1523/JNEUROSCI.2658-14.2015.
Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was responsible for the enhanced memory function, the NE prodrug l-threo-dihydroxyphenylserine was administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for treatment in individuals with DS and dementia.
仅由设计药物激活的设计受体（DREADDs）是研究大脑中离散神经元群体的新型强大工具。我们已使用DREADDs来刺激唐氏综合征（DS）模型Ts65Dn小鼠中的退化神经元。患有DS的个体发展出阿尔茨海默病（AD）神经病理学，并且从30多岁和40多岁开始患痴呆症的风险升高。患有DS的个体经常表现出工作记忆缺陷以及蓝斑（LC）去甲肾上腺素（NE）神经元的退化。据认为，LC退化先于其他与AD相关的神经元损失，并且LC去甲肾上腺素能完整性对于执行功能、工作记忆和注意力很重要。先前的研究表明，增强LC的药物可以减缓AD病理学的进展，包括淀粉样蛋白聚集、氧化应激和炎症。我们已经表明，Ts65Dn小鼠中的LC退化导致过度的记忆丧失和神经元退化。我们使用了一种DREADD，hM3Dq，通过腺相关病毒在合成启动子PRSx8的控制下注入LC，通过外源性给予惰性DREADD配体氯氮平 - N - 氧化物来选择性刺激LC神经元。对LC - NE的DREADD刺激提高了Ts65Dn小鼠在新物体识别任务中的表现并减少了多动，而对对照组没有显著的行为影响。为了证实去甲肾上腺素能递质系统负责增强的记忆功能，在Ts65Dn小鼠和正常染色体同窝对照小鼠中给予NE前药l - 苏式 - 二羟基苯丝氨酸，并产生了相似的行为结果。因此，NE刺激可能预防Ts65Dn小鼠的记忆丧失，并且可能对DS和痴呆症个体的治疗具有前景。
