Absence of VGLUT3 Expression Leads to Impaired Fear Memory in Mice

eNeuro. 2023 Feb 23;10(2):ENEURO.0304-22.2023. 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.

Keywords: aversive memories; pattern separation; spatial memory; vesicular glutamate transporter type 3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fear* / physiology
  • Glutamic Acid / metabolism
  • Memory Disorders
  • Mice
  • Synaptic Transmission*
  • Vesicular Glutamate Transport Proteins / metabolism


  • Vesicular Glutamate Transport Proteins
  • Glutamic Acid