Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling.
Notch1 Regulates Hippocampal Plasticity Through Interaction with the Reelin Pathway, Glutamatergic Transmission and CREB Signaling.
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Notch1通过与Reelin通路、谷氨酸能传递和CREB信号相互作用调控海马可塑性
DOI：
10.3389/fncel.2015.00447
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发表时间：
2015
影响因子：
5.3
通讯作者：
Alberi L
中科院分区：
文献类型：
--
作者：
Brai E;Marathe S;Astori S;Fredj NB;Perry E;Lamy C;Scotti A;Alberi L
Notch信号在成人脑功能如突触可塑性、记忆和嗅觉等方面起着至关重要的作用。一些报告表明，这一途径参与了神经退行性痴呆。然而，到目前为止，成熟神经元中Notch活性的潜在机制仍未解决。在这项工作中，我们研究了Notch如何调节突触增强并有助于建立小鼠的记忆。我们观察到Notch1是一种突触后受体，与Reelin受体、载脂蛋白E受体2(ApoER2)和离子型受体N-甲基-D-天冬氨酸受体(NMDAR)具有功能相互作用。在海马CA区靶向缺失Notch1通过影响Dab1的表达来影响Reelin信号转导，并损害通过Reelin刺激实现的突触增强。进一步分析表明，Notch1的缺失影响NMDAR的表达和组成，但不影响AMPAR。通过下调CaMKII及其二级和三级信使，谷氨酸能信号进一步受损，导致cAMP反应元件结合(CREB)信号减少。我们的结果证明Notch1是突触可塑性和记忆形成机制的重要调节因子。这些发现强调了这种信号受体可能参与了痴呆症。在本文中，我们提出了一种Notch1依赖可塑性的机制，该机制可能是Notch1在记忆形成中作用的基础：Notch1与另一条重要的发育途径Reelin级联相互作用。NOTCH1同时调节NMDAR的表达和组成。NOTCH1影响一系列细胞事件，最终导致CREB激活。
Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade. Notch1 regulates both NMDAR expression and composition. Notch1 influences a cascade of cellular events culminating in CREB activation.