VPA targets Mid1 to improve disrupted retrograde axonal transport in hippocampal neurons and alleviate lithium manganate-induced learning and memory dysfunction

INTRODUCTION: Lithium manganate (LMO) is a new type of pollutant that is extensively applied in the manufacture of lithium-ion batteries. Accumulating evidence indicates that both manganese (Mn) and lithium (Li) can cross the blood-brain barrier and accumulate within the hippocampus. However, the neurotoxic effects of LMO on hippocampal core functions and the involved molecular mechanisms are still unclear. OBJECTIVES: This study observed whether LMO exposure impairs hippocampus-dependent learning and memory in mice and investigated related mechanisms and intervention strategies. METHODS: for 28 and 45 days, corresponding approximately to 3 and 5 human years. In parallel, in vitro co-exposure models were established using HT-22 cells and primary hippocampal neurons treated with Mn and Li. Neurobehavioral, neuropathological, live-cell imaging-based assays were used to assess learning and memory impairment, neuronal damage, and retrograde axonal transport dysfunction. RNA-sequencing and molecular biology approaches were conducted to explore and validate mechanisms. Mid1 silencing/knockdown and valproic acid (VPA) treatment were used to assess whether modulation of Mid1-related changes attenuates LMO-induced neurotoxicity. RESULTS: The results demonstrated that LMO exposure impaired learning and memory in mice. Mechanistically, LMO or Mn and Li co-exposure up-regulates the E3 ubiquitin ligase Mid1 which promotes the degradation of dynein light chain family members Dynlrb2 and Dynlt4 through the ubiquitin-proteasome pathway. This disruption impairs retrograde axonal transport in hippocampal neurons, resulting in neuronal injury and ultimately compromising learning and memory function in mice. Suppression of Mid1 ,or VPA treatment significantly improved the observed neuronal damage and the expression levels of factors related to axonal retrograde transport. CONCLUSION: This study indicates that LMO inhalation exposure is associated with learning and memory deficits and hippocampal neuronal injury, accompanied by Mid1-related ubiquitin-proteasome alterations and disrupted retrograde axonal transport.