Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner.
Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner.
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DOI：
10.1016/j.neulet.2016.05.043
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发表时间：
2016-08-03
影响因子：
2.5
通讯作者：
Dell'Acqua ML
中科院分区：
文献类型：
--
作者：
Freund RK;Graw S;Choo KS;Stevens KE;Leonard S;Dell'Acqua ML
α7烟碱乙酰胆碱受体（nAChR）功能降低与精神分裂症患者大脑皮层依赖性感觉加工和学习记忆受损有关虽然在C57/B16背景下敲除编码α 7 nAChR的Chrna 7基因会导致认知测量的变化，但先前的研究发现对这些小鼠的海马突触可塑性几乎没有影响。然而，精神分裂症是一种多基因疾病，其中特定基因突变和整体遗传背景之间的复杂相互作用可能在确定表型突变中起重要作用。因此，我们比较了敲除α 7 nAChR对C57/B16和C3 H小鼠突触可塑性的影响，这两种小鼠的基础α 7 nAChR表达水平不同。C3 H小鼠的α7纯合子缺失通常表达较高的α 7 nAChR水平，导致海马CA 1突触的长时程增强（LTP）受损，而C3 H α7杂合子小鼠保持稳健的LTP。与此相反，C57小鼠中的纯合α7缺失，通常表达较低的α 7 nAChR水平，并没有改变LTP，正如以前对该品系的报道。因此，LTP所需的Chrna 7表达的阈值在两种菌株中可能不同。听觉门控是一种用于识别精神分裂症相关感觉处理缺陷的大脑皮层依赖性行为模式，在C3 H α7基因敲除小鼠中测量听觉门控异常，证实听觉门控也需要α 7 nAChR表达。我们的研究强调了遗传背景对突触可塑性调节的重要性，并可能有助于理解精神障碍中α 7 nAChR功能障碍的人类研究中的遗传和认知异质性。
Reduced α7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the Chrna7 gene encoding the α7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the α7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal α7nAChR expression levels. Homozygous α7 deletion in C3H mice, which normally express higher α7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H α7 heterozygous mice maintained robust LTP. In contrast, homozygous α7 deletion in C57 mice, which normally express lower α7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of Chrna7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H α7 knockout mice confirming that auditory gating also requires α7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of α7nAChR dysfunction in mental disorders.