Interlinked role of GSK3β and KCNQ/Kv7 channels in dementia: Therapeutic Advances with KCNQ/Kv7 channel activators and GSK3β Inhibitors

The establishment of new synaptic connections driven by synaptic plasticity at excitatory synapses is a prerequisite for learning and memory in the brain. Growing evidence suggests that disruption in synaptic plasticity mechanisms contributes to various forms of dementia. The GSK3β signaling system significantly influences dementia. Amyloid beta (Aβ) can activate GSK3β, so establishing a destructive feedback loop that can further exacerbate the condition of dementia. Potassium ion channels (KCNQ/Kv7), particularly Kv7.2 and Kv7.4, regulate neuronal excitability and synaptic plasticity, mitochondrial Ca2+ overload and mitophagy. KCNQ/Kv7.2 channel dysfunction contributes to hyperexcitability and synaptic dysfunction, exacerbating dementia. Hyperactive GSK3β phosphorylates Kv7.2 channels, leading to KCNQ channel inactivation. Research indicates that combining GSK3β inhibitors with KCNQ/Kv7 channel activators yields a synergistic effect, enhancing neuroprotection and stabilizing neuronal excitability, thus providing a multi-faceted approach in dementia management. Challenges remain in fully elucidating the mechanisms underlying the GSK3β and KCNQ/Kv7 interactions, alongside issues regarding their specificity and safety. This review examines the crosstalk between GSK3β and KCNQ/Kv7 channels and the management of dementia with synergistic combination of GSK3β inhibitors and KCNQ/Kv7 channel activators.