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一个基本目标。突触强度的改变是神经元网络电路中记忆形成的基础，而稳态突触可塑性将神经元的变化维持在生理限度内。我们知道谷氨酸能n -甲基- d -天冬氨酸受体（NMDAR）和-氨基-3-羟基-5-甲基-4-异恶唑烯丙酸受体（AMPAR）都在突触可塑性的两种形式中起关键作用。然而，在突触可塑性过程中控制这些受体的分子机制仍有待完全确定。这两种受体的关键调节剂是酪氨酸磷酸酶STEP（纹状体富集磷酸酶），它通过去磷酸化和促进NMDAR和AMPAR的内化来抵消突触强化。虽然我们知道STEP与体内平衡可塑性有关，但维持其作用的分子机制仍有待确定。此外，我们仍然忽略了STEP如何与AMPAR相互作用，这促使我们发现可能代表STEP和AMPAR之间缺失环节的新分子。神经素-1蛋白（NLG1）是由STEP调控的一个有趣的候选蛋白，有几个原因。与STEP一样，NLG1位于谷氨酸突触的突触后膜，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的磷酸化状态在一个独特的酪氨酸（Y782）诱导突触形成和稳定，但调控Y782的蛋白的身份仍然未知。该项目的中心假设是NLG1是STEP信号级联的一个新的分子组成部分，参与稳态突触可塑性的建立和记忆的形成。我们将根据三个具体目标来验证这一假设：***目的1：揭示STEP和NLG1在体外稳态突触可塑性中的蛋白相互作用。***目的2：通过STEP证明NLG1的去磷酸化可改变体外记忆形成的突触可塑性。***目的3：评估STEP和NLG1结合是否影响体内稳态突触可塑性和记忆形成。这个研究项目的长期目标是了解突触可塑性的基本分子机制。这项研究的好处是很多的，并且有很强的潜力揭示参与稳态突触可塑性的关键信号通路。对控制突触可塑性的分子机制的更清晰的理解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 -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.********