Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer’s disease (AD). Increases in cytosolic noradrenaline (NA) concentration and MAO-A activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since re-uptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP) and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca ²⁺ ] _i increases, subsequently increasing Ca ²⁺ -dependent MAO-A activity and NA-autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating re-uptake of autocrine-released NA. The suppression of α2A-AR internalization has a strong translational potential for AD.