Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7-deficient mice
Loss of forebrain cholinergic neurons and impairment in spatial learning and memory in LHX7-deficient mice
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DOI：
10.1111/j.1460-9568.2005.04141.x
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发表时间：
2005-06-01
影响因子：
3.4
通讯作者：
Pachnis, V
中科院分区：
文献类型：
--
作者：
Fragkouli, A;Hearn, C;Pachnis, V
确定哺乳动物大脑中指定神经网络的遗传决定因素对于理解最终控制认知功能的分子和细胞机制至关重要。在这里，我们通过用LacZ报告子替换外显子3-5，生成了lim同源结构域编码基因Lhx7的靶等位基因。在健康、可育且前脑没有明显细胞缺陷的杂合动物中，b-半乳糖苷酶活性再现了野生型Lhx7位点的表达模式。然而，纯合突变小鼠表现出前脑胆碱能神经元（fcn）的严重缺陷，而其他类型的前脑神经元则未受影响。使用LacZ报告基因作为标记，我们发现lhx7缺陷小鼠的FCN祖细胞存活，但不能在纹状体中产生胆碱能中间神经元和在基底前脑中产生胆碱能投射神经元。对一系列空间和非空间学习和记忆任务的行为分析表明，Lhx7突变体的FCN消融与严重的空间缺陷有关，而非空间学习和记忆的损害仅轻微。此外，我们在突变动物中没有发现长时程增强缺陷，这表明fcnn调节海马功能独立于其存储信息的能力。总的来说，我们的实验表明Lhx7的表达是参与空间信息处理的胆碱能前脑神经元的规范或分化所必需的。
The identification of the genetic determinants specifying neuronal networks in the mammalian brain is crucial for the understanding of the molecular and cellular mechanisms that ultimately control cognitive functions. Here we have generated a targeted allele of the LIM-homeodomain-encoding gene Lhx7 by replacing exons 3-5 with a LacZ reporter. In heterozygous animals, which are healthy, fertile and have no apparent cellular deficit in the forebrain, b-galactosidase activity reproduces the pattern of expression of the wild-type Lhx7 locus. However, homozygous mutant mice show severe deficits in forebrain cholinergic neurons (FCNs), while other classes of forebrain neurons appear unaffected. Using the LacZ reporter as a marker, we show that in LHX7-deficient mice FCN progenitors survive but fail to generate cholinergic interneurons in the striatum and cholinergic projection neurons in the basal forebrain. Analysis of behaviour in a series of spatial and non-spatial learning and memory tasks revealed that FCN ablation in Lhx7 mutants is associated with severe deficits in spatial but only mild impairment of non-spatial learning and memory. In addition, we found no deficit in long-term potentiation in mutant animals, suggesting that FCNs modulate hippocampal function independently of its capacity to store information. Overall our experiments demonstrate that Lhx7 expression is required for the specification or differentiation of cholinergic forebrain neurons involved in the processing of spatial information.