The glutaminase inhibitor JHU-083 mitigates cognitive dysfunction in a mouse model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is characterized by symptoms including re-experiencing, avoidance, hyperarousal, and negative alterations in cognition and mood as defined by DSM-5. It is frequently accompanied by comorbid conditions such as anxiety, depression, and cognitive impairments, which are primarily attributed to abnormal hippocampal neuronal damage and impaired synaptic plasticity. Glutaminase (GLS), a key enzyme in the synthesis of glutamate within the brain, plays a role in regulating neurodevelopment and synaptic excitability. However, the impact of GLS inhibition on neuronal repair and synaptic plasticity in PTSD models remains unclear. We established a traumatic stress model using the single prolonged stress combined with foot shock (SPS&S) method, which simulates aspects of trauma-related behaviors, such as anxiety-like, depressive-like, and cognitive impairments. We evaluated the efficacy of the GLS inhibitor JHU-083 in PTSD model mice by assessing indicators related to anxiety and depression levels, cognitive function, neuronal damage, and synaptic plasticity. Our results show that JHU-083 treatment alleviates behavioral abnormalities in PTSD model mice. The therapeutic effect of JHU-083 is associated with improved hippocampal neuronal repair and enhanced synaptic plasticity. Furthermore, JHU-083 may enhance neurocognitive function and ameliorate hippocampal synaptic deficits in PTSD model mice through the PI3K signaling pathway. These findings suggest that the GLS inhibitor JHU-083 can improve anxiety and cognitive dysfunction in mice exhibiting PTSD-like behaviors, likely by enhancing neuronal repair and synaptic plasticity in the hippocampus via modulation of the PI3K signaling pathway.