Glycogen synthase kinase-3beta affects size of dentate gyrus and species-typical behavioral tasks in transgenic and knockout mice.

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-3ß isoform on hippocampal size, number of doublecortin-positive cells, and hippocampal-dependent behaviors. Both GSK-3ß transgenic mice (GSK-3ß[S9A] mice) and GSK-3ß neuron-specific knockout (GSK-3ß(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-3ß[S9A] mice, but not in GSK-3ß(n-/-) mice. We conclude that GSK-3ß 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.