Reversing Pathophysiology in Fragile X Syndrome Mice by Promoting PGC-1α and Mitochondrial Functions

Abstract

Fragile X syndrome (FXS) is the leading cause of intellectual disabilities and autism, but a disease-modifying strategy remains unavailable. Recent studies have suggested reduced mitochondrial functions in FXS. However, the mechanisms underlying mitochondrial defects and their impact on FXS pathophysiology remain largely unclear. Here, we reveal a reduction in the mitochondrial master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) in the mouse model of FXS, the Fmr1 knockout (KO) mice. We show that this impairment is caused by the inactivity of the transcription factor cAMP-response element-binding protein (CREB) in Fmr1 KO mice. Using the small molecule ZLN005, which induces AMP-activated protein kinase (AMPK)- and CREB-dependent elevation of PGC-1 in Fmr1 KO mice, we observed significantly increased mitochondrial functions and dynamics in cultured neurons in vitro and in the hippocampus in vivo. Furthermore, ZLN005 elicited a wide range of beneficial effects in Fmr1 KO mice, including enhanced inhibitory synaptic transmission, reduced circuit hyperexcitability, improved hippocampal synaptic plasticity, reduced cortical gamma-band oscillations, and improved interhemispheric coherence. Most importantly, we observed improved cognition and reduced autism-like behaviors in ZLN005-treated Fmr1 KO mice. Together, our findings identify AMPK-CREB signaling and PGC-1 as promising and selective therapeutic targets for FXS and reveal the broad impact of restoring PGC-1 on FXS pathophysiology. One Sentence SummaryPromoting PGC-1 Reverses FXS Pathophysiology.