BHLHE40 modulates post-traumatic stress disorder behaviors with the involvement of the PI3K/AKT signaling pathway

Post-traumatic stress disorder (PTSD) is closely related to the exposure to traumatic events and results in the structural and functional changes of hippocampus. Human basic helix-loop-helix family member e40 (BHLHE40) was reported to be implicated with neuron maturity and neuronal differentiation. The present study aimed to reveal the role of BHLHE40 on single-prolonged stress (SPS) model of PTSD in mice. The morris water maze test, open field test and contextual fear test were conducted to assess memory deficits, anxiety-like behaviors, and freezing of mice. Western blot was performed to identify proteins and reveal their levels in hippocampal tissues. We found that mice receiving SPS exhibited increased anxiety-like behaviors, memory deficits, and prolonged freezing time. The protein levels of BHLHE40 were downregulated in the hippocampal tissues of SPS mice. SPS reduced the protein levels of glutamate receptors, while overexpression of BHLHE40 promoted glutamate receptor protein levels in SPS mice. Moreover, BHLHE40 overexpression activated the PI3K/AKT pathway. BHLHE40 overexpression ameliorated the SPS-induced PTSD-like behavioral deficits. Overall, BHLHE40 promotes glutamate receptor protein levels to ameliorate PTSD-like behaviors with the involvement of the PI3K/AKT pathway. This novel discovery may provide a potential target for the improvement of PTSD.