Silibinin exerts antidepressant effects by improving neurogenesis through BDNF/TrkB pathway.

Classic antidepressants benefit depression patients partially by improving neurogenesis and/or brain-derived neurotrophic factor (BDNF)/TrkB pathway which were impaired in depression. In this study, we demonstrated that Silibinin (SLB), a polyphenolic flavanoid from Silybum marianum, ameliorated reserpinized mouse depressant-like behaviors. The antidepressants of SLB administration was associated with increased neural stem cells (NSCs) proliferation and further confirmed in BDNF/TrkB signaling transduction. SLB treatment reversed the decreased expression levels of BDNF and its receptor TrkB, and the reduced activation of downstream target proteins including phosphorylated extracellular-regulated protein kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB) in depressived hippocampus. Furthermore, intracerebroventricular injection of GNF5837, a TrkB antagonist, abrogated antidepressant-like effects of SLB in mice along with the improved NSC proliferation, as well as enhanced levels of p-ERK and p-CREB in mice hippocampus. Taken together, these results suggest that SLB may exert antidepressant effects through BDNF/TrkB signaling pathway to improve NSC proliferation in acute depression.

Anxiolytic effect of CPEB1 knockdown on the amygdala of a mouse model of inflammatory pain.

Anxiety disorders are a category of mental disorders characterized by feelings of anxiety, stress, and fear attached to various sources. However, their pathogenesis is complicated and has not been fully elucidated. The amygdala is a vital brain region that regulates anxiety and mental disorders. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) mediates the extension of the mRNA polyadenylation tail and facilitates the translation of target RNA. CPEB1 is closely related to neuronal diseases, such as Fragile X Syndrome, learning and memory disorders, and chronic pain. In this study, the role of CPEB1 in anxiety development was determined in a pain-mediated anxiety mouse model. The anxiety model was established in mice by injecting with Complete Freund's Adjuvant (CFA) into the hindpaw. CFA injection then led to anxiety-like behaviors and increased the CPEB1 levels in the mouse basolateral amygdala (BLA). CPEB1 enhancement facilitated the translation of GluA1, GluN2A, GluN2B, PSD95, and GABA receptors, which disturbed the E/I balance in the BLA as shown by enhanced excitatory presynaptic release and reduced inhibitory presynaptic release. CPEB1 knockdown with AAV-CPEB1-shRNA alleviated the anxiety-like behaviors but not the pain-like behaviors by enhancing inhibitory transmission in the BLA of model mice. The data suggest that CPEB1 participates in anxiety development by regulating excitatory/inhibitory synaptic transmission in the BLA.

Elevated progranulin contributes to synaptic and learning deficit due to loss of fragile X mental retardation protein.

Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome.