HuR Is Critical For The Depressive-like Behaviors In Mice

Depression is one of the most common mental disorders which threat human beings in the world and is caused by a combination of multiple factors.After the treatment with antidepressants,57% of patients will relapse due to the drug resistance.Futhermore,there is no effective treatment for 30 to 40% of patients with major depression.Therefore,it is imperative toinvestigate the underlying of depression and develop effective treatment strategies.Previous work indicate that exposure to stress leads to depression in humans and rodents,but the underlying mechanisms remains unclear.RNA binding proteins(RBPs)are involved in the regulation of neuronal development and neuroplasticity.HuR(Human antigen R)regulates numerous cellular stress responses,so we speculate that HuR is is critical for the stress-induce depression in the brain.In this study,we first examined the expression pattern of HuR in the brain of adult mice by Western-Blot and and found that HuR is highly expressed at mature developmental stage.By performing previous established assays for depression,we observed that conditional knockout of HuR in excitatory pyramidal neurons of the cortex decreases sensitivity to depression in mice.Golgi staining experiments and electrophysiological patch clamp experiments showed that dendritic spine density and neurotransmitter release are increased in HuR knockout mice.These results suggest that knockout of HuR in the cortex is critical for sensitivity to depression in mice and HuR regulates depression via modulating neuronal development.Upon further inspection,with application of chronic restraint stress on mice,we examined the expression of HuR in the prefrontal cortex by Western-Blot and found that the expression of HuR is increased in stressed compared to control mice.Using viral stereotactic injection and behavioral tests,we confirmed that HuR in the prefrontal cortex is critical for depression-like behavior induced by stress adult mice.Golgi staining experiments and electrophysiological experiments showed that dendritic spines density and neurotransmitter release in prefrontal cortical neurons are increased in HuR conditional knockout mice.These data indicate that HuR is requird for the synaptic structural and functional plasticity induced by chronic stress.In summary,our results indicate that HuR is involved in the regulation of depression by regulating neuronal development and synaptic plasticity in mice.