Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington's disease model.
Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington's disease model.
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DOI：
10.1038/ncomms15592
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发表时间：
2017-05-30
影响因子：
16.6
通讯作者：
Girault JA
中科院分区：
文献类型：
--
作者：
Giralt A;Brito V;Chevy Q;Simonnet C;Otsu Y;Cifuentes-Díaz C;de Pins B;Coura R;Alberch J;Ginés S;Poncer JC;Girault JA
棘和兴奋性突触的结构和功能受多种信号网络的动态控制。虽然酪氨酸磷酸化参与，其调节和重要性还没有得到很好的理解。在这里，我们研究Pyk 2的作用，一个非受体的钙依赖性蛋白酪氨酸激酶在海马高度表达。海马相关学习和CA 1长时程增强在Pyk 2缺陷小鼠中严重受损，并与NMDA受体、PSD-95和树突棘的改变相关。在培养的海马神经元中，Pyk 2在决定PSD-95富集和棘密度方面具有自磷酸化依赖性和非依赖性作用。Pyk 2水平在患有亨廷顿的个体的海马体中以及在该疾病的R6/1小鼠模型中降低。使R6/1小鼠海马中的Pyk 2水平正常化挽救了记忆缺陷、脊柱病理学和PSD-95定位。我们的研究结果揭示了Pyk 2在脊柱结构和突触功能中的作用，并表明其缺陷导致了亨廷顿病的认知障碍。几种激酶调节棘的形态和可塑性。在这里，作者表明酪氨酸激酶Pyk 2调节海马可塑性，并有助于认知和海马可塑性缺陷的亨廷顿病小鼠模型。
The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington's disease cognitive impairments. Several kinases regulate spine morphology and plasticity. Here, the authors show that the tyrosine kinase Pyk2 regulates hippocampal plasticity and contributes to cognitive and hippocampal plasticity deficits in a mouse model of Huntington's disease.