FTO alleviates chronic restraint stress-induced cognitive deficits and depressive-like behaviors via regulating PI3K/Akt signaling, autophagy, and synaptic plasticity.

OBJECTIVE: This study aimed to investigate whether Fat mass and obesity-associated protein (FTO) alleviated chronic restraint stress (CRS)-induced neurobehavioural deficits and elucidated the potential mechanisms.

METHODS: C57BL/6 mice were randomly assigned to five groups: Control, CRS, CRS + AAV-mediated FTO overexpression, CRS + AAV-empty, CRS + FTO-AAV + LY294002. Depressive-like behaviors and cognitive function were assessed followed by CRS procedure. Western blot was used to analyze PI3K/Akt signaling, autophagy markers (LC3, Beclin-1), and synaptic proteins (PSD-95, Synaptophysin). Immunofluorescence staining was conducted to observe ZO-1 and occluding. Transmission electron microscopy (TEM) was employed to observe synaptic ultrastructure. Nissl staining was performed to assess neuronal survival.

RESULTS: Mice subjected to CRS exhibited depressive-like behaviors, cognitive deficits, decreased FTO expression, inhibiting of PI3K/Akt signaling, disrupted hippocampal autophagy, reduction of synaptic protein levels, enhancing neuronal loss, and promoting blood brain barrier (BBB) disruption. However, FTO overexpression in hippocampus significantly alleviated cognitive impairment and depressive-like behaviors, activating PI3K/Akt pathway, normalized autophagy, enhanced synaptic protein expression, preserved BBB integrity, and exerted neuroprotective effect in hippocampal neurons. Besides, TEM confirmed that synaptic density were preserved in mice treated with FTO overexpression. However, these neuroprotective effects of FTO were evidently reversed followed by PI3K inhibitor (LY294002) administration.

CONCLUSIONS: FTO attenuated CRS-induced cognitive impairment and depressive-like behaviors through regulating PI3K/Akt signaling, autophagy, synaptic plasticity, neuronal survival, and BBB integrity. These findings highlight that FTO could be a potential therapeutic target for CRS-related neuropsychiatric disorders.