Fragile X syndrome is an inheritable type of mental incapacity brought on by lack of fragile X psychological retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP induced overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis issue receptor ligand. Within the current examine, we discovered that progranulin mRNA and protein had been upregulated within the medial prefrontal cortex of Fmr1 knock-out mice.
In Fmr1 knock-out mice, elevated progranulin induced inadequate dendritic backbone pruning and late-phase long-term potentiation within the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored backbone morphology and reversed behavioural deficits, together with impaired worry reminiscence, hyperactivity, and motor inflexibility in Fmr1 knock-out mice.
Progranulin elevated ranges of phosphorylated glutamate ionotropic receptor GluA1 and nuclear issue kappa B in cultured wild-type neurons. Tumour necrosis issue receptor 2 antibody perfusion blocked the results of progranulin on GluA1 phosphorylation; this outcome signifies that tumour necrosis issue receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression.
Nonetheless, excessive basal degree of progranulin in Fmr1 knock-out mice prevented additional facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis issue receptor 2/nuclear issue kappa B signalling restored synaptic plasticity and reminiscence deficits in Fmr1 knock-out mice. These findings recommend that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis issue receptor 2 signalling pathway could also be a putative therapeutic goal for bettering cognitive deficits in fragile X syndrome.