VDAC activation inhibits hippocampal plasticity via NLRP3 inflammasome & caspase-1: modulation by allopregnanolone enantiomers

Abstract

Voltage-dependent anion channels (VDACs) are the most abundant proteins in the outer mitochondrial membrane (OMM) and key regulators of mitochondrial function under physiological and pathological conditions. These channels are modulated by multiple agents and are known binding sites for neuroactive steroids (NAS) including allopregnanolone (AlloP). Using erastin, an agent that promotes VDAC activation by preventing inhibition by tubulin, we assessed the impact of VDAC activation on hippocampal function. Brief erastin administration had no effect on basal transmission but completely inhibited induction of long-term potentiation (LTP) in the Schaffer collateral pathway of rat hippocampal slices. This LTP inhibition was prevented by VBIT-4, an agent that inhibits VDAC oligomerization. VDAC-mediated LTP inhibition was also prevented by inhibitors of the NLRP3 inflammasome and caspase-1, downstream effectors of VDACs, but not by inhibition of cGAS-STING, narrowing the neuroinflammatory pathways involved. Similarly, effects of erastin were prevented by AlloP and at lower concentrations by its unnatural enantiomer (ent-AlloP), an agent that unlike AlloP has little effect on GABAA receptors. Erastin also inhibited memory formation in a hippocampal-dependent form of one-trial learning and these effects were prevented by VBIT-4 and ent-AlloP, but not by a non-sedating dose of AlloP. These results have relevance for understanding the role of VDACs as mediators of neuronal stress and for the further development of NAS as neurotherapeutics and modulators of cellular stress. SIGNIFICANCE STATEMENTVoltage-dependent anion channels (VDACs) are important regulators of mitochondrial function, playing roles in cellular metabolism, stress responses and neuroinflammation, and contribute to the pathogenesis of neuropsychiatric illnesses. Here we show that erastin, an agent that activates VDACs initiates specific neuroinflammatory responses to acutely disrupt synaptic plasticity in the rodent hippocampus and abrogate learning. These adverse effects are prevented by the neuroactive steroids allopregnanolone, which binds VDACs and is used clinically for postpartum depression, and its unnatural enantiomer, suggesting that these agents could have therapeutic effects in a broad range of brain illnesses.