Dynamic Range of GSK3α Not GSK3β Is Essential For Bidirectional Synaptic Plasticity at Hippocampal CA3-CA1 Synapses

Glycogen synthase kinase-3 (GSK3), particularly the isoform GSK3, has been implicated in a wide range of physiological systems and neurological disorders including Alzheimer's Disease. However, the functional importance of GSK3 has been largely untested. The multifunctionality of GSK3 limits its potential as a drug target because of inevitable side effects. Due to its greater expression in the CNS, GSK3 rather than GSK3 has also been assumed to be of primary importance in synaptic plasticity. Here, we investigate bidirectional long-term synaptic plasticity in knockin mice with a point mutation in GSK3 or GSK3 that prevents their inhibitory regulation. We report that only the mutation in GSK3 affects long-term potentiation (LTP) and depression (LTD). This stresses the importance of investigating isoform specificity for GSK3 in all systems and suggests that GSK3 should be investigated as a drug target in cognitive disorders including Alzheimer's Disease. (c) 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.