Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Mol Neurodegener. 2013 Jan 17;8:3. doi: 10.1186/1750-1326-8-3.
Accumulation of β-amyloid (Aβ) and cholinergic deficiency are two prominent features of Alzheimer's disease (AD). To understand how Aβ-induced dysfunction of the nicotinic system may contribute to cognitive impairment in AD, we examined the effect of Aβ on nicotinic regulation of synaptic transmission and neuronal excitability in prefrontal cortex (PFC), a brain region critical for cognitive processes.
We found that activation of nicotinic acetylcholine receptors (nAChRs) with nicotine increased the inhibitory postsynaptic currents recorded in PFC pyramidal neurons, which was associated with the nicotine-induced increase in the excitability of PFC layer I GABAergic interneurons. Both effects of nicotine were disrupted by Aβ. However, Aβ did not impair nicotinic regulation of excitatory neurotransmission in PFC interneurons. The nicotinic effect on synaptic inhibition was also lost in transgenic mice with five familial Alzheimer's disease mutations. Inhibiting PKC attenuated nicotinic regulation of inhibitory, but not excitatory, neurotransmission.
Our study suggests that Aβ selectively impairs nicotinic regulation of inhibitory inputs to PFC pyramidal neurons, which might be due to its interference with PKC activation. Thus, in the PFC circuits of AD, the balance between inhibition and excitation under the control of nAChRs may be disturbed by Aβ.
β-淀粉样蛋白（Aβ）的积累和胆碱能缺乏是阿尔茨海默病（AD）的两个突出特征。为了了解 Aβ 诱导的烟碱型乙酰胆碱受体（nAChRs）功能障碍如何导致 AD 中的认知障碍，我们研究了 Aβ 对前额叶皮层（PFC）中烟碱型乙酰胆碱受体调节突触传递和神经元兴奋性的影响，PFC 是与认知过程相关的关键脑区。
我们发现，尼古丁激活 nAChRs 可增加 PFC 锥体神经元记录的抑制性突触后电流，这与尼古丁诱导的 PFC 层 I GABA 能中间神经元兴奋性增加有关。Aβ 破坏了尼古丁对 PFC 中间神经元兴奋性递质传递的调节作用。具有五个家族性阿尔茨海默病突变的转基因小鼠中，尼古丁对突触抑制的作用也丧失了。抑制蛋白激酶 C（PKC）可减弱尼古丁对抑制性但不兴奋性神经传递的调节作用。
我们的研究表明，Aβ 选择性损害 PFC 锥体神经元抑制性传入的烟碱型乙酰胆碱受体调节作用，这可能是由于其干扰了 PKC 的激活。因此，在 AD 的 PFC 回路中，Aβ 可能会破坏 nAChRs 控制下的抑制与兴奋之间的平衡。
