Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Department of Molecular Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Birmannsgasse 8, 4055 Basel, Switzerland.
Curr Biol. 2021 Feb 8;31(3):527-539.e7. doi: 10.1016/j.cub.2020.10.069. Epub 2020 Nov 30.
Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (K) channels are potential regulators of memory and may be linked to age-dependent neuronal disfunction. MinK-related peptides (MiRPs) are conserved transmembrane proteins modulating K channels; however, their possible role in the regulation of memory and age-dependent memory decline are unknown. Here, we show that, in C. elegans, mps-2 is the sole member of the MiRP family that controls exclusively long-term associative memory (LTAM) in AVA neuron. In addition, we demonstrate that mps-2 also plays a critical role in age-dependent memory decline. In young adult worms, mps-2 is transcriptionally upregulated by CRH-1/cyclic AMP (cAMP)-response-binding protein (CREB) during LTAM, although the mps-2 baseline expression is CREB independent and instead, during aging, relies on nhr-66, which acts as an age-dependent repressor. Deletion of nhr-66 or its binding element in the mps-2 promoter prevents age-dependent transcriptional repression of mps-2 and memory decline. Finally, MPS-2 acts through the modulation of the K2.1/KVS-3 and K2.2/KVS-4 heteromeric potassium channels. Altogether, we describe a conserved MPS-2/KVS-3/KVS-4 pathway essential for LTAM and also for a programmed control of physiological age-dependent memory decline.
活动依赖性神经元内在兴奋性和突触强度的持久变化是学习和记忆的基础。电压门控钾 (K) 通道是记忆的潜在调节剂，可能与年龄相关的神经元功能障碍有关。MinK 相关肽 (MiRPs) 是保守的跨膜蛋白，调节 K 通道；然而，它们在记忆调节和与年龄相关的记忆衰退中的可能作用尚不清楚。在这里，我们表明，在 C. elegans 中，mps-2 是 MiRP 家族的唯一成员，它专门控制 AVA 神经元中的长时联想记忆 (LTAM)。此外，我们还证明 mps-2 也在与年龄相关的记忆衰退中起着关键作用。在年轻的成年蠕虫中，mps-2 在 LTAM 期间被 CRH-1/环腺苷酸 (cAMP)-反应结合蛋白 (CREB) 转录上调，尽管 mps-2 的基础表达不受 CREB 调控，而是在衰老过程中依赖 nhr-66，nhr-66 作为一种与年龄相关的抑制剂发挥作用。nhr-66 或其在 mps-2 启动子中的结合元件的缺失可防止 mps-2 的与年龄相关的转录抑制和记忆衰退。最后，MPS-2 通过调节 K2.1/KVS-3 和 K2.2/KVS-4 异源二聚体钾通道起作用。总之，我们描述了一种保守的 MPS-2/KVS-3/KVS-4 途径，对于 LTAM 以及对生理与年龄相关的记忆衰退的程序性控制都是必不可少的。
