mGluR2/3 receptor agonist LY379268 alleviates PTSD-like fear memories by downregulating the CaMKII/CREB signaling pathway in the hippocampus and prefrontal cortex.

Post-traumatic stress disorder (PTSD) is a mental health condition marked by fear memories triggered by life-threatening traumatic events. The formation and consolidation of these fear memories are central to PTSD, making it important to understand the underlying neurobiological mechanisms that regulate memory plasticity. In this context, LY379268, a selective mGluR2/3 agonist, induces presynaptic long-term depression (LTD) and modulates excitatory transmission, potentially affecting memory consolidation. Propranolol, a β-adrenergic antagonist, similarly influences fear memory through synaptic signaling in stress-responsive brain regions. Both compounds thus serve as tools to investigate how synaptic plasticity and neuronal signaling contribute to the regulation of fear- and anxiety-related memory. In this study, rats underwent single prolonged stress and contextual fear conditioning (SPS&CFC). After validating the model, 6 µM LY379268 or 10 µM propranolol were injected into the lateral ventricle during the memory consolidation phase. Anxiety and fear memory were assessed through open field tests, elevated plus maze, and freezing behavior observations. Additionally, CaMKII/CREB signaling pathway proteins were analyzed via western blotting and immunofluorescence, while synaptic ultrastructure in the hippocampus (HIP) and prefrontal cortex (PFC) was examined using transmission electron microscopy. We found rats subjected to SPS&CFC showed increased anxiety and fear memory, with heightened levels of CaMKII, ERK, and CREB proteins in the HIP and PFC, alongside synaptic damage. However, treatment with 6 μM LY379268 improved these conditions, restoring CaMKII, ERK, CREB levels, and synaptic structure. This suggests that LY379268 may influence memory related to anxiety and stress in PTSD by modulating synaptic plasticity through the CaMKII/CREB pathway, providing a basis for further investigation into the underlying neurobiological mechanisms.