Fragile X syndrome (FXS) is an inheritable neuropsychological disease caused by silence of the fmr1 gene and the deficiency of Fragile X mental retardation protein (FMRP). Patients present neuronal alterations that lead to severe intellectual disability and altered sleep rhythms. However, the neural circuit mechanisms underlying FXS remain unclear. Previous studies have suggested that metabolic glutamate and gamma-aminobutyric acid (GABA) receptors/circuits are two counter-balanced factors involved in FXS pathophysiology. More and more studies demonstrated that attenuated GABAergic circuits in the absence of FMRP are critical for abnormal progression of FXS. Here, we reviewed the changes of GABA neural circuits that were attributed to intellectual-deficient FXS, from several aspects including deregulated GABA metabolism, decreased expressions of GABA receptor subunits, and impaired GABAergic neural circuits. Furthermore, the activities of GABA neural circuits are modulated by circadian rhythm of FMRP metabolism and reviewed the abnormal condition of FXS mice or patients.

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Chronic stress is one of the most potent risk factors for the onset of major depressive disorder. Chronic unpredictable mild stress results in reduced synaptic proteins and depression-like behaviors in rodent models. However, the upstream molecule that senses the demand for synaptic proteins and initiates their synthesis under chronic stress remains unknown. In our research, chronic unpredictable mild stress reduced the expression of PPP4R3A in the prefrontal cortex and hippocampus in mice. Selective knockout of Ppp4r3a in the cortex and hippocampus mimicked depression- and anxiety-like behavioral effects of chronic stress in mice. Notably, Ppp4r3a deficiency led to down-regulated mTORC1 signaling, which resulted in reduced synthesis of synaptic proteins and impaired synaptic functions. On the contrary, overexpression of Ppp4r3a in the cortex and hippocampus protected against behavioral and synaptic deficits induced by chronic stress in a PPP4R3A-mTORC1-dependent manner. Rapamycin treatment of Ppp4r3a-overexpressing neurons blocked the regulatory effect of Ppp4r3a on the synthesis of synaptic proteins by directly inhibiting mTORC1. Overall, our results revealed a regulatory role of Ppp4r3a in driving synaptic protein synthesis in chronic stress.

Fig. 4a in Manuscript ID#JOCI-D-19-00318 has been revised due to the replacement of immunoblot lane of β-catenin by Zo-1 in NHA group. Please see below corrected version.

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