Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β

Abstract

In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (K_ATP) are involved in neural function and plasticity. Moreover, alterations in K_ATP activity and expression have been observed in Alzheimer’s disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether K_ATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a K_ATP blocker (Tolbutamide) or a K_ATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both K_ATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that K_ATP are involved in Aβ-induced pathology and they heighten the potential role of K_ATP modulation as a plausible therapeutic strategy against AD.