Zimmerman Amber J, Serrano-Rodriguez Antonio, Sun Melody, Wilson Sandy J, Linsenbardt David N, Brigman Jonathan L, Weick Jason P
Department of Neurosciences, University of New Mexico School of Medicine, 915 Camino de Salud NE, Fitz Hall 145, Albuquerque, NM, 87131, USA.
Present Address: Division of Sleep Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, 19104, USA.
Mol Brain. 2024 Dec 18;17(1):95. doi: 10.1186/s13041-024-01158-7.
The vast majority of gene mutations and/or gene knockouts result in either no observable changes, or significant deficits in molecular, cellular, or organismal function. However, in a small number of cases, mutant animal models display enhancements in specific behaviors such as learning and memory. To date, most gene deletions shown to enhance cognitive ability generally affect a limited number of pathways such as NMDA receptor- and translation-dependent plasticity, or GABA receptor- and potassium channel-mediated inhibition. While endolysosomal trafficking of AMPA receptors is a critical mediator of synaptic plasticity, mutations in genes that affect AMPAR trafficking either have no effect or are deleterious for synaptic plasticity, learning and memory. NSG2 is one of the three-member family of Neuron-specific genes (NSG1-3), which have been shown to regulate endolysosomal trafficking of a number of proteins critical for neuronal function, including AMPAR subunits (GluA1-2). Based on these findings and the largely universal expression throughout mammalian brain, we predicted that genetic knockout of NSG2 would result in significant impairments across multiple behavioral modalities including motor, affective, and learning/memory paradigms. However, in the current study we show that loss of NSG2 had highly selective effects on associative learning and memory, leaving motor and affective behaviors intact. For instance, NSG2 KO animals performed equivalent to wild-type C57Bl/6n mice on rotarod and Catwalk motor tasks, and did not display alterations in anxiety-like behavior on open field and elevated zero maze tasks. However, NSG2 KO animals demonstrated enhanced recall in the Morris water maze, accelerated reversal learning in a touch-screen task, and accelerated acquisition and enhanced recall on a Trace Fear Conditioning task. Together, these data point to a specific involvement of NSG2 on multiple types of associative learning, and expand the repertoire of pathways that can be targeted for cognitive enhancement.
绝大多数基因突变和/或基因敲除要么不会导致可观察到的变化，要么会在分子、细胞或机体功能上产生显著缺陷。然而，在少数情况下，突变动物模型在学习和记忆等特定行为方面表现出增强。迄今为止，大多数已显示出能增强认知能力的基因缺失通常只影响有限的一些通路，如N-甲基-D-天冬氨酸（NMDA）受体和翻译依赖性可塑性，或γ-氨基丁酸（GABA）受体和钾通道介导的抑制作用。虽然α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的内溶酶体运输是突触可塑性的关键介质，但影响AMPA受体运输的基因突变要么没有影响，要么对突触可塑性、学习和记忆有害。NSG2是神经元特异性基因（NSG1-3）三成员家族之一，已证明它能调节许多对神经元功能至关重要的蛋白质的内溶酶体运输，包括AMPA受体亚基（GluA1-2）。基于这些发现以及其在整个哺乳动物大脑中的广泛普遍表达，我们预测NSG2基因敲除会导致多种行为模式出现显著损伤，包括运动、情感和学习/记忆范式。然而，在当前研究中我们发现，NSG2缺失对联想学习和记忆有高度选择性影响，而运动和情感行为未受影响。例如，NSG2基因敲除动物在转棒试验和Catwalk运动任务中的表现与野生型C57Bl/6n小鼠相当，在旷场试验和高架零迷宫任务中焦虑样行为也未出现改变。然而，NSG2基因敲除动物在莫里斯水迷宫试验中表现出增强的记忆回忆能力，在触屏任务中加速了逆向学习，在痕迹恐惧条件反射任务中加速了习得并增强了记忆回忆。总之，这些数据表明NSG2在多种类型的联想学习中具有特定作用，并扩展了可用于认知增强的通路范围。
