Hypobaric Hypoxia-Induced Learning and Memory Impairment: Elucidating the Role of Small Conductance Ca2+-Activated K+ Channels

Hypobaric Hypoxia (HH) is well-known to cause cognitive impairment and synaptic dysfunction which results in neurodegeneration. Although the role of small conductance calcium-activated potassium channels (SK channels) has been reported in synaptic plasticity, cognition and different neurological disorders; however, the precise role of SK channels in HH-induced memory impairment remains yet to be explored. We, therefore, hypothesized the pivotal role of SK channels in HH-induced cognitive decline and investigated the SK channel expression during different duration of HH exposure (Control, 1, 3, 7 and 14 days) at mRNA and protein level in male Sprague-Dawley rats. Further the role of SK channels in spatial memory and neurodegeneration were explored by inhibiting SK channel through Apamin (a known SK channel blocker). Results from the present study revealed that acute exposure of HH for 3 days leads to significant increase in expression of SK1 and SK3 channels at mRNA and protein levels, which upon chronic exposure restored to normal. Remarkably, SK2 channel expression showed gradual increase from 3 days till 14 days. Immunohistochemical analysis revealed similar pattern in different regions of the hippocampus. Additionally, SK channel inhibition with Apamin prevented HH-induced neurodegeneration and memory impairment as evident from decreased number of Fluoro Jade-positive cells, pyknotic cells, and caspase-3 expression and improved performance in the Morris water maze task. Thus, the present study demonstrates that SK channels play a crucial role in HH-induced cognitive decline and neurodegeneration.