Department of Neurology and Neurological Sciences, Stanford Medical School, Stanford, CA 94305, USA.
Sci Transl Med. 2009 Nov 18;1(7):7ra17. doi: 10.1126/scitranslmed.3000258.
Down syndrome (trisomy 21) is the most common cause of mental retardation in children and leads to marked deficits in contextual learning and memory. In rodents, these tasks require the hippocampus and are mediated by several inputs, particularly those originating in the locus coeruleus. These afferents mainly use norepinephrine as a transmitter. To explore the basis for contextual learning defects in Down syndrome, we examined the Ts65Dn mouse model. These mice, which have three copies of a fragment of mouse chromosome 16, exhibited significant deficits in contextual learning together with dysfunction and degeneration of locus coeruleus neurons. However, the postsynaptic targets of innervation remained responsive to noradrenergic receptor agonists. Indeed, despite advanced locus coeruleus degeneration, we were able to reverse contextual learning failure by using a prodrug for norepinephrine called l-threo-3,4-dihydroxyphenylserine, or xamoterol, a beta(1)-adrenergic receptor partial agonist. Moreover, an increased gene dosage of App, in the context of Down syndrome, was necessary for locus coeruleus degeneration. Our findings raise the possibility that restoring norepinephrine-mediated neurotransmission could reverse cognitive dysfunction in Down syndrome.
唐氏综合征（21 三体）是儿童智力迟钝最常见的原因，导致情景学习和记忆明显缺陷。在啮齿动物中，这些任务需要海马体，并由多个输入介导，特别是那些起源于蓝斑核的输入。这些传入纤维主要使用去甲肾上腺素作为递质。为了探讨唐氏综合征情景学习缺陷的基础，我们研究了 Ts65Dn 小鼠模型。这些小鼠有三条来自小鼠 16 号染色体的片段，表现出明显的情景学习缺陷，同时蓝斑核神经元功能障碍和退化。然而，支配的突触后靶标仍然对去甲肾上腺素受体激动剂有反应。事实上，尽管蓝斑核退化严重，我们仍能通过使用一种称为 l-苏-3,4-二羟基苯丙氨酸的去甲肾上腺素前体药物或β1-肾上腺素受体部分激动剂 xamoterol 来逆转情景学习失败。此外，唐氏综合征中 App 的基因剂量增加是蓝斑核退化所必需的。我们的研究结果提出了这样一种可能性，即恢复去甲肾上腺素介导的神经传递可能会逆转唐氏综合征的认知功能障碍。
