Absence of VGLUT3 expression leads to impaired fear memory in mice.

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 Post-Traumatic 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 (ACh), serotonin (5-HT) or GABA.To understand the involvement of VGLUT3-dependent cotransmission 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 due to 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.