Connexin43 In Medial Prefrontal Cortex And Hippocampus Regulates Depression-like Behavior

Depression is the most common mood disorder.Over a lifetime,the incidence of depression is 12%to 17%.According to the report of the World Health Organization,there are 340 million people suffering from depression worldwide,and 10 to 20 million patients have suicidal tendency every year.According to its development trend,depression will become the first cause of disability by 2020.The pathogenesis of depression is still unknown.Antidepressant drugs developed on the basis of monoamine neurotransmitter theory have good efficacy and safety,but they still face many severe challenges.Therefore,to clarify the pathogenesis of depression and find new antidepressant drugs or treatment with better therapeutic effects is the key scientific issue of current depression research.The central nervous system contains two types of nerve cells:neuron and glial cell.Clinical and animal studies suggested that abnormal astrocyte function is associated with depression.Astrocytes are connected to each other by gap junction channels（GJCs）.In astrocytes,the major subunit that constitutes GJCs is connexin43（Cx43）.Postmortem studies of patients with major depression and suicide showed that mRNA levels of Cx43 in the prefrontal lobe and hippocampus were down-regulated.To verify that Cx43 on astrocytes is involved in the regulation of depression-like behavior,we constructed a specific astrocyte knockout of Cx43（Aldh1l1-creERT2;Gjal f/f）mice.Western blot showed that Cx43 protein expression was decreased.The behavioral tests showed that there was no difference in the total distance of movement within 5 minutes in the open-field test,and the cumulative time in the central area decreased.There was no difference in the total distance within 30 minutes.The elevated plus maze,the mice accumulated less time in the open arm..In the experiment of sucrose preference test,the sucrose preference ratio of mice decreased.In the forced swimming experiment,the cumulative immobility time of the mice increased.The results showed that Aldh111-creERT2;Gja1f/f mice exhibited depression-like and anxiety-like behavior.To investigate whether Cx43 on mPFC and hippocampus astrocytes is involved in the regulation of depression-like behavior,C57BL/6J mice were given mPFC or hippocampus injection of shRNA virus to knock down Cx43 on astrocytes.The behavioral tests showed that:in the open-field test,there was no difference in the total distance of movement within 5 minutes,and the cumulative time in the central area decreased.There was no difference in the total distance within 30 minutes.The elevated plus maze,the mice accumulated less time in the open arm.In the experiment of sucrose preference test,the sucrose preference ratio of mice decreased.In the forced swimming experiment,the cumulative immobility time of the mice increased.In summary,Cx43 in the medial prefrontal cortex and hippocampus regulates depressionlike behavior.Aldh111-creert2 was detected by microdialysis.The concentration of ATP in Aldh111-creERT2;Gjal f/f mice hippocampus was lower than that in the control group.After injecting ATP into the hippocampus,the cumulative immobility time of the forced swimming test mice decreased.These results suggested that Cx43 of hippocampal astrocytes regulates depression-like behavior through ATP.