FGF21 Exhibits Neuroprotective Effects by Promoting 5-HT_1AR-FGFR1 Heteroreceptor Complexes and Triggering MEK_1/2-ERK_1/2 Signaling Pathway

Approaches of promoting a neural milieu permissive for plasticity and resilience against neuronal injury are important strategies for the treatment of a range of neurological disorders. Fibroblast growth factor 21 (FGF21) which is known for its role as a potent regulator of glucose and energy metabolism has also proved to be neuroprotective against various mental diseases. However, the underlying molecular mechanisms remain elusive. Here, we report a study of the neuroprotective effects of FGF21 by promoting 5-HT_1AR-FGFR1 heteroreceptor formation and triggering MEK_1/2-ERK_1/2 signaling pathway in normal or abnormal neurological conditions. First, the in vitro cellular experiments demonstrated that FGF21 exerted a protective effect against glutamate-induced cytotoxicity and promoted cell differentiation and growth. Then, in wild-type and FGF21^-/- mice, exogenous FGF21 promoted FGFR1-5-HT_1AR heteromers formation in the CA3 and dentate gyrus region of the hippocampus and activated MEK_1/2-ERK_1/2 signaling. Coordinately, FGF21 exerted similar influences in the hippocampi of IBA-induced neurological injury mice or combined stress-exposed mice. Besides, FGF21 treatment activated the phosphorylation of FGFR1 and elevated the expression of synaptophysin in these mice with neurological injury or combined stress exposure. These results illustrated that FGF21 alleviated neurological impairment through FGFR1-5-HT_1AR heteromer and ERK_1/2 signal activation and suggested that the regulation of FGFR1-5-HT_1AR heteromers and MEK_1/2/ERK_1/2 pathway may play a key role in mediating the neuroprotective effects of FGF21 against various neurodegeneration conditions.