Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function

了解突触可塑性的分子机制是神经生物学的基本目标。突触强度的改变是神经元网络回路记忆形成的基础，而稳态突触可塑性将神经元的变化维持在生理范围内。我们知道，谷氨酸能N-甲基-D-天冬氨酸受体(NMDAR)和a-amino-3-hydroxyle-5-methyl-4-isoxazolepropionic酸受体(AMPAR)都参与了这两种形式的突触可塑性。然而，在突触可塑性过程中控制这些受体的分子机制仍然需要完全建立。这两种受体的一个关键调节因子是酪氨酸磷酸酶步骤(纹状体富含磷酸酶)，它通过去磷酸化和促进NMDAR和AMPAR的内化来抵消突触增强。虽然我们知道STEP与动态平衡可塑性有关，但维持其作用的分子机制仍有待建立。此外，我们仍然忽略了STEP与AMPAR的相互作用，这促使我们发现了可能代表STEP和AMPAR之间缺失的一环的新分子。 神经连接蛋白-1(NLG1)是一个有趣的候选蛋白，受到STEP的调节，原因有几个。与STEP一样，NLG1位于谷氨酸突触的突触后膜上，通过激活NMDAR和AMPAR参与突触连接的形成和稳定。虽然我们知道NLG1在一种独特的酪氨酸(Y782)处的磷酸化状态可以诱导突触的形成和稳定，但调控Y782的蛋白质的同一性仍然不清楚。该计划的中心假设是，NLG1是STEP信号级联中的一个新的分子成分，参与建立内稳态突触可塑性和记忆形成。我们将根据三个具体目标来检验这一假设： 目的：揭示STEP和NLG1在体外动态平衡突触可塑性中的蛋白质相互作用。 目的：证明NLG1的去磷酸化改变了记忆形成的突触可塑性。 目的：探讨STEP和NLG1结合对体内稳态突触可塑性和记忆形成的影响。 这项研究的长期目标是了解突触可塑性的基本分子机制。这项研究的好处是多方面的，并有很强的潜力来揭示涉及内稳态突触可塑性的关键信号通路。更清楚地理解支配突触可塑性的分子机制将为大脑如何形成和存储新信息带来新的见解。

Understanding the molecular mechanisms underlying synaptic plasticity is a fundamental goal in neurobiology. Alteration in synaptic strength underlies memory formation in the neuronal network circuitry, whereas homeostatic synaptic plasticity maintains neuronal changes within physiological limit. We know that the glutamatergic N-methyl-D-aspartate receptor (NMDAR) and a-amino-3-hydroxyle-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) are both critically involved in both forms of synaptic plasticity. However, the molecular mechanisms controlling these receptors during synaptic plasticity still need to be fully established. A key modulator of both receptors is the tyrosine phosphatase STEP (STriatal Enriched Phosphatase) that counteract synaptic strengthening by dephosphorylating and promoting internalization of the NMDAR and AMPAR. Although we know that STEP is involved in homeostatic plasticity, the molecular mechanisms sustaining its action remain to be established. Moreover, we still ignore how STEP interacts with the AMPAR, which prompts us to uncover novel molecules that might represent the missing link between STEP and AMPAR. The protein Neuroligin-1 (NLG1) is an interesting candidate regulated by STEP for several reasons. Like STEP, NLG1 is located at the post-synaptic membrane of glutamate synapses, and is involved in the formation and stabilization of synaptic connections by activating the NMDAR and AMPAR. Although we know that the phosphorylation state of NLG1at a unique tyrosine (Y782) induced synapse formation and stabilization, the identity of the proteins that regulate Y782 is still unknown. The central hypothesis of this program is that NLG1 is a new molecular component of the STEP signaling cascade involved in the establishment of homeostatic synaptic plasticity and memory formation. We will test this hypothesis according to three specific objectives: Objective 1: Uncover the protein interaction of STEP and NLG1 during homeostatic synaptic plasticity in vitro. Objective 2: Demonstrate that dephosphorylation of NLG1 by STEP alters synaptic plasticity underlying memory formation in vitro. Objective 3: Evaluate if STEP and NLG1 binding affects homeostatic synaptic plasticity and memory formation in vivo. The long-term objective of this research program is to understand the fundamental molecular mechanisms of synaptic plasticity. The benefits of this research are numerous and have a strong potential to uncover key signaling pathways involved in homeostatic synaptic plasticity. A clearer comprehension of the molecular mechanisms that govern synaptic plasticity will bring new insights on how the brain forms and stores novel information.