Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice
Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice
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DOI：
10.1128/mcb.01339-14
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发表时间：
2015-05-01
影响因子：
5.3
通讯作者：
Ohnishi, Hiroshi
中科院分区：
文献类型：
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作者：
Kusakari, Shinya;Saitow, Fumihito;Ohnishi, Hiroshi
Shp2（Src同源2结构域蛋白酪氨酸磷酸酶2）调节神经细胞分化。然而，它也在有丝分裂后的神经元中表达，并且Shp2的突变与以精神发育迟滞为特征的临床综合征相关。在这里，我们表明，条件性敲除（cKO）小鼠缺乏Shp2特异性有丝分裂后前脑神经元表现出异常的行为，包括多动症。在Shp2 cKO小鼠的大脑皮层和海马中，新诱导的即刻早期基因表达和细胞外信号调节激酶（Erk）活化减弱，表明神经元活性降低。与此相反，消融Shp2增强高K+诱导的Erk激活培养的皮层神经元和突触体，而它抑制脑源性生长因子诱导的培养的神经元。在Shp2 cKO小鼠的海马切片中，强直后增强和成对脉冲易化分别减弱和增强。突变小鼠在Morris水迷宫中也表现出短暂的记忆形成障碍。我们的数据表明，Shp2有助于调节有丝分裂后前脑神经元的Erk激活和突触可塑性，从而控制运动活动和记忆形成。
Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.