LAMP2A-mediated neuronal hyperexcitability by enhancing NKAβ1 degradation underlies depression-induced allodynia

Painful physical symptoms in major depressive disorder (MDD) patients lead to poor outcomes during MDD treatment. Here, we report that decreased Na⁺/K⁺-ATPase β1 subunit (NKAβ1) expression in anterior cingulate cortex glutamatergic (ACC^Glu) neurons promotes ion dyshomeostasis, leading to hyperactivity of ACC^Glu-insular cortex circuits in chronic stress mice. This ultimately primes allodynia. Mechanistically, we reveal that chronic stress strengthens LAMP2A-driven chaperone-mediated autophagy (CMA) and subsequently promotes the degradation of NKAβ1. We further identify NKAβ1 as a CMA substrate. Accordingly, genetically LAMP2A loss in ACC^Glu neurons reverses chronic-stress-induced neuronal hyperexcitability, subsequently ameliorating allodynia. Additionally, we develop a trans-activating transcription (TAT)-LAMP2A peptide that significantly alleviates depression-induced allodynia. Taken together, our results reveal a mechanistic connection between CMA and neuronal excitability. TAT-LAMP2A peptide intervention, by disturbing CMA-dependent NKAβ1 elimination, could be a potential pharmacological treatment for depression-induced allodynia and further facilitate the efficacy of antidepressant treatment.