Glycogen synthase kinase-3 (GSK-3), a multifunctional serine-threonine kinase, is an important regulator in numerous signaling pathways and processes including adult brain neurogenesis. GSK-3 (mal)functioning was implicated in many diseases, in particular neurological and behavioral disorders. We investigated the impact of altered levels of the GSK-3β isoform on hippocampal size, number of doublecortin-positive cells, and hippocampal-dependent behaviors. Both GSK-3β transgenic mice (GSK-3β[S9A] mice) and GSK-3β neuron-specific knockout (GSK-3β(n-/-)) mice, showed reduced size of the dentate gyrus (DG) and were impaired in three hippocampal-dependent, species-typical behavioral tasks: digging, marble burying and nest building. We further demonstrate that the number of differentiating, doublecortin-positive new neurons is reduced in GSK-3β[S9A] mice, but not in GSK-3β(n-/-) mice. We conclude that GSK-3β activity must be critically controlled to allow wild type-like volume of the dentate gyrus and for normal execution of hippocampal-dependent, species-typical behavior.
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