Lithium Attenuates Scopolamine-Induced Memory Deficits with Inhibition of GSK-3β and Preservation of Postsynaptic Components

Cholinergic dysfunction plays a crucial role in the memory deterioration of Alzheimer's disease, but the molecular mechanism is not fully understood. By employing a widely recognized cholinergic dysfunction rat model that was produced by intraperitoneal injection of scopolamine, we investigated the mechanisms underlying scopolamine-induced memory deficits. We found that scopolamine caused spatial learning and memory deficits that involved activation of glycogen synthase kinase-3 beta (GSK-3 beta) and impairments of dendrite arborization and spine formation/maturation associated with alterations of AMPAR, Homer1, and CREB. Pretreatment by intraperitoneal injection of lithium, an inhibitor of GSK-3, for one week prevented the synaptic changes and the learning and memory deficits induced by scopolamine. Lithium treatment also activated cholineacetyl-transferase and inhibited acetylcholinesterase, which might have also contributed to the improved memory. Our findings suggest that GSK-3 beta may be a key molecular mediator of cholinergic synaptic dysfunction, and that inhibition of GSK-3 beta by lithium may be promising in protecting cholinergic synaptic functions.