Regulation of Learning by EphA Receptors: a Protein Targeting Study
Regulation of Learning by EphA Receptors: a Protein Targeting Study
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DOI：
10.1523/jneurosci.19-21-09538.1999
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发表时间：
1999-11
期刊：
影响因子：
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通讯作者：
R. Gerlai;N. Shinsky;A. Shih;P. Williams;J. Winer;M. Armanini;B. Cairns;J. Winslow;Wei-qiang Gao;H. Phillips
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作者：
R. Gerlai;N. Shinsky;A. Shih;P. Williams;J. Winer;M. Armanini;B. Cairns;J. Winslow;Wei-qiang Gao;H. Phillips
EphA 家族受体酪氨酸激酶及其肝配蛋白 A 配体参与大脑发育过程中轴突连接的模式化，但到目前为止，这些分子在成熟大脑中的作用尚未阐明。在这里，我们发现 EphA5 受体及其肝配蛋白-A 配体（2 和 5）在成年小鼠海马中表达，并且 EphA5 蛋白以磷酸化形式存在。由于没有针对 EphA 受体的药物制剂，我们设计了重组免疫粘附素，其特异性结合肝配蛋白-A 配体（拮抗剂）的受体结合位点或 EphA 受体（激动剂）的配体结合位点，从而靶向 EphA 功能。我们证明，海马内输注 EphA 拮抗剂免疫粘附素会导致两种行为范式的表现受损，即 T 迷宫自发交替和情境依赖性恐惧条件反射，对海马功能敏感，而通过输注激动剂免疫粘附素激活 EphA 会增强这些任务的表现。由于这两种行为任务具有不同的动机、知觉和运动要求，因此我们推断这些变化不是由这些表现因素引起的，而是由认知改变引起的。我们还发现基因表达和与行为结果相关的突触功效的电生理测量的双向变化。因此，EphA 受体及其配体被认为是成年哺乳动物大脑可塑性的介质。
EphA family receptor tyrosine kinases and their ephrin-A ligands are involved in patterning axonal connections during brain development, but until now a role for these molecules in the mature brain had not been elucidated. Here, we show that both the EphA5 receptor and its ephrin-A ligands (2 and 5) are expressed in the adult mouse hippocampus, and the EphA5 protein is present in a phosphorylated form. Because there are no pharmacological agents available for EphA receptors, we designed recombinant immunoadhesins that specifically bind to the receptor binding site of the ephrin-A ligand (antagonist) or the ligand binding site of the EphA receptor (agonist) and thus target EphA function. We demonstrate that intrahippocampal infusion of an EphA antagonist immunoadhesin leads to impaired performance in two behavioral paradigms, T-maze spontaneous alternation and context-dependent fear conditioning, sensitive to hippocampal function, whereas activation of EphA by infusion of an agonist immunoadhesin results in enhanced performance on these tasks. Because the two behavioral tasks have different motivational, perceptual, and motor requirements, we infer the changes were not caused by these performance factors but rather to cognitive alterations. We also find bidirectional changes in gene expression and in electrophysiological measures of synaptic efficacy that correlate with the behavioral results. Thus, EphA receptors and their ligands are implicated as mediators of plasticity in the adult mammalian brain.