Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Neuroscience Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), Paris 75005, France.
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal QC H4H 1R3, Quebec, Canada.
eNeuro. 2023 Feb 23;10(2). doi: 10.1523/ENEURO.0304-22.2023. Print 2023 Feb.
Fear is an emotional mechanism that helps to cope with potential hazards. However, when fear is generalized, it becomes maladaptive and represents a core symptom of posttraumatic stress disorder (PTSD). Converging lines of research show that dysfunction of glutamatergic neurotransmission is a cardinal feature of trauma and stress related disorders such as PTSD. However, the involvement of glutamatergic co-transmission in fear is less well understood. Glutamate is accumulated into synaptic vesicles by vesicular glutamate transporters (VGLUTs). The atypical subtype, VGLUT3, is responsible for the co-transmission of glutamate with acetylcholine, serotonin, or GABA. To understand the involvement of VGLUT3-dependent co-transmission in aversive memories, we used a Pavlovian fear conditioning paradigm in VGLUT3 mice. Our results revealed a higher contextual fear memory in these mice, despite a facilitation of extinction. In addition, the absence of VGLUT3 leads to fear generalization, probably because of a pattern separation deficit. Our study suggests that the VGLUT3 network plays a crucial role in regulating emotional memories. Hence, VGLUT3 is a key player in the processing of aversive memories and therefore a potential therapeutic target in stress-related disorders.
恐惧是一种帮助应对潜在危险的情绪机制。然而，当恐惧被泛化时，它就变得适应不良，成为创伤后应激障碍（PTSD）的核心症状之一。越来越多的研究表明，谷氨酸能神经传递功能障碍是创伤和应激相关障碍（如 PTSD）的一个主要特征。然而，谷氨酸能共传递在恐惧中的参与还不太清楚。谷氨酸通过囊泡谷氨酸转运体（VGLUTs）被积累到突触小泡中。非典型亚型 VGLUT3 负责与乙酰胆碱、血清素或 GABA 共传递谷氨酸。为了了解 VGLUT3 依赖性共传递在厌恶记忆中的参与，我们在 VGLUT3 小鼠中使用了条件性恐惧学习范式。我们的结果表明，这些小鼠的上下文恐惧记忆更高，尽管有消退促进作用。此外，VGLUT3 的缺失会导致恐惧泛化，可能是由于模式分离缺陷所致。我们的研究表明，VGLUT3 网络在调节情绪记忆中起着至关重要的作用。因此，VGLUT3 是处理厌恶记忆的关键因素，因此也是应激相关障碍的潜在治疗靶点。
