The therapeutic potential and mechanisms of targeting the PTBP1/Nogo-A/NgR axis in PTSD induced by single prolonged stress in mice.

Abstract

The pathophysiology of post-traumatic stress disorder (PTSD) shows notable associations with compromised hippocampal neurophysiology. Notwithstanding ongoing debates, PTBP1 knockdown (KD) demonstrates the capacity to drive glia-to-neuron reprogramming, potentially offering therapeutic benefits for some neurodegenerative pathologies. However, PTBP1 KD can upregulate the expression of Nogo-A by alternative splicing, triggering the inhibition of nerve regeneration. Currently, the role of PTBP1 in PTSD remains unknown. Here we sought to elucidate the neurorestorative effects of modulating the PTBP1/Nogo-A/NgR axis in a mouse model of PTSD established through the single prolonged stress paradigm, and the mechanisms were further investigated through a series of experiments including pathological and molecular detection. The results indicated that PTBP1 KD ameliorates PTSD-like behaviors in mice by balancing Bcl-2/Bax expression and suppressing Caspase-3 splicing activation to inhibit hippocampal neuronal apoptosis, enhancing synaptic plasticity through upregulating PSD95 and SYN1, increasing dendritic spine density and stabilizing axonal architecture via elevated NF200 expression. However, compared with single prolonged stress alone, PTBP1 KD potentiates the activation of Nogo-A/NgR pathway, adversely impacting both dendritic morphology and axonal elongation. Therefore, we proposed a combined KD of PTBP1 and NgR to counteract the adverse effects mediated by Nogo-A signal activation, effectively promoting dendritic growth and axonal extension in hippocampal neurons of PTSD mice. Our findings underscore the potential and limitations of PTBP1 as a therapeutic target and propose a novel method for PTSD treatment through combined target intervention of PTBP1 and NgR. This study provides a theoretical foundation for multitarget intervention strategies in the treatment of PTSD and related disorders.