Influence of Large Conductance Ca2+- and Voltage-Activated K+ Channels (BK) on Synaptic Plasticity in Young and Aged Mice

Abstract

Impaired synaptic plasticity is one cause for cognitive decline in neurodegenerative diseases like Alzheimer’s disease. While BK mutations have been linked to cognitive impairment, their exact impact on synaptic plasticity remains elusive. BK’s role in synaptic plasticity was investigated using hippocampal pyramidal neuron-specific conditional BK knockout mice cKO mediated by T29.1-Cre and littermate controls CTRL.

Western-blot and immunofluorescence identified effective and hippocampus-specific BK depletion in cKO. Beam Walk Test and Open Field Test verified the ability of these mice to perform behavioral memory tasks. cKO consistently displayed delayed learning during Morris Water Maze acquisition phase and limited memory retrieval during probe trials. In animals with advanced age, learning deficits could no longer be detected, probably because the smaller difference is masked by declining cognition. In vivo findings in young mice were additionally corroborated by the lack of electrically and chemically induced Long-Term Potentiation measured by the initial slope of fEPSPs and the absence of increased AMPAR phosphorylation at S845-GluA1, a surrogate parameter for physiological LTP. Furthermore, cLTP induction in primary hippocampal neurons led to BK-mediated reduction in intracellular potassium concentration ([K+]i) as observed using genetically encoded potassium ion indicator. Decreased [K+]i was accompanied by increased frequencies of neuronal Ca2+ oscillations, as detected by FURA-2. Both, [K+]i reduction and Ca2+ oscillations were sensitive to DL-AP5 and Nifedipine, indicating potential functional interactions between NMDAR, LTCC and BK during LTP. Despite a strong and prolonged K+ efflux during cLTP, no change in membrane potential was observed via DiBAC4(3) in either BK+/+ neurons or PAX-inhibited BK+/+ neurons. This is probably due to the rapid repolarization by the Ca2+ oscillations.

The data suggest BK-dependent K+ efflux as critical to support hippocampal synaptic plasticity by maintaining Ca2+ influx through NMDA receptors and LTCC during LTP. This suggests BK modulation as a potential therapeutic option to treat cognitive impairment.