Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Biol Psychiatry. 2012 Jan 15;71(2):120-8. doi: 10.1016/j.biopsych.2011.09.011. Epub 2011 Oct 25.
Nicotinic signaling in prefrontal layer VI pyramidal neurons is important to the function of mature attention systems. The normal incorporation of α5 subunits into α4β2* nicotinic acetylcholine receptors augments nicotinic signaling in these neurons and is required for normal attention performance in adult mice. However, the role of α5 subunits in the development of the prefrontal cortex is not known.
We sought to answer this question by examining nicotinic currents and neuronal morphology in layer VI neurons of medial prefrontal cortex of wild-type and α5 subunit knockout (α5(-/-)) mice during postnatal development and in adulthood.
In wild-type but not in α5(-/-) mice, there is a developmental peak in nicotinic acetylcholine currents in the third postnatal week. At this juvenile time period, the majority of neurons in all mice have long apical dendrites extending into cortical layer I. Yet, by early adulthood, wild-type but not α5(-/-) mice show a pronounced shift toward shorter apical dendrites. This cellular difference occurs in the absence of genotype differences in overall cortical morphology.
Normal developmental changes in nicotinic signaling and dendritic morphology in prefrontal cortex depend on α5-comprising nicotinic acetylcholine receptors. It appears that these receptors mediate a specific developmental retraction of apical dendrites in layer VI neurons. This finding provides novel insight into the cellular mechanisms underlying the known attention deficits in α5(-/-) mice and potentially also into the pathophysiology of developmental neuropsychiatric disorders such as attention-deficit disorder and autism.
前额叶皮层 VI 层锥体神经元中的烟碱信号对于成熟注意系统的功能很重要。正常的α5 亚基掺入到α4β2*烟碱型乙酰胆碱受体中增强了这些神经元中的烟碱信号，并对成年小鼠的正常注意力表现是必需的。然而，α5 亚基在前额叶皮层发育中的作用尚不清楚。
我们通过检查野生型和α5 亚基敲除（α5(-/-)）小鼠内侧前额叶皮层 VI 层神经元中的烟碱电流和神经元形态，来回答这个问题，这些检查在出生后发育和成年期间进行。
在野生型小鼠中，但不在α5(-/-)小鼠中，第三周龄后出现烟碱型乙酰胆碱电流的发育高峰。在这个幼年期，大多数小鼠的神经元都有长的树突伸向皮质层 I。然而，在成年早期，野生型小鼠而非α5(-/-)小鼠表现出明显的向较短的树突的转变。这种细胞差异发生在整体皮质形态没有基因型差异的情况下。
前额叶皮层中烟碱信号和树突形态的正常发育变化依赖于包含α5 的烟碱型乙酰胆碱受体。似乎这些受体介导了 VI 层神经元中树突的特定发育回缩。这一发现为已知的α5(-/-)小鼠注意力缺陷的细胞机制提供了新的见解，也为注意力缺陷障碍和自闭症等发育性神经精神障碍的病理生理学提供了新的见解。
