Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity
Long-Term α1A-Adrenergic Receptor Stimulation Improves Synaptic Plasticity, Cognitive Function, Mood, and Longevity
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DOI：
10.1124/mol.111.073734
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发表时间：
2011-10-01
影响因子：
3.6
通讯作者：
Perez, Dianne M.
中科院分区：
文献类型：
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作者：
Doze, Van A.;Papay, Robert S.;Perez, Dianne M.
α（1）-肾上腺素能受体（α（1）AR）在认知和情绪中的作用是有争议的，可能是由于过去使用非选择性药物的结果。最近显示α（1A）AR激活增加神经发生，这与认知和情绪有关。我们研究了长期α（1A）AR刺激的影响，使用转基因小鼠表达α（1A）AR的组成型活性突变体（CAM）形式。CAM-α（1A）AR小鼠在学习和记忆的几种行为模型中表现出增强。相比之下，α（1A）AR基因敲除的小鼠表现出较差的认知功能。与野生型（WT）小鼠相比，CAM-α（1A）AR小鼠的海马脑切片显示出基础突触传递、成对脉冲易化和长时程增强增加。用α（1A）AR选择性激动剂cirazoline治疗的WT小鼠也显示出增强的认知功能。此外，与WT小鼠相比，CAM-α（1A）AR小鼠在几项行为测试中表现出抗抑郁和较少焦虑的表型。此外，CAM-α（1A）AR小鼠的寿命比WT小鼠长10%。我们的研究结果表明，长期α（1A）AR刺激改善突触可塑性，认知功能，情绪和寿命。这可能提供一个潜在的治疗靶点，用于抵消与衰老和神经系统疾病相关的认知功能和情绪下降。
The role of alpha(1)-adrenergic receptors (alpha(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. alpha(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term alpha(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the alpha(1A)AR. CAM-alpha(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the alpha(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-alpha(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the alpha(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-alpha(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-alpha(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term alpha(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.