GSK-3β and MMP-9 Cooperate in the Control of Dendritic Spine Morphology

Changes in the morphology of dendritic spines are prominent during learning and in different neurological and neuropsychiatric diseases, including those in which glycogen synthase kinase-3 beta (GSK-3 beta) has been implicated. Despite much evidence of the involvement of GSK-3 beta in functional synaptic plasticity, it is unclear how GSK-3 beta controls structural synaptic plasticity (i.e., the number and shape of dendritic spines). In the present study, we used two mouse models overexpressing and lacking GSK-3 beta in neurons to investigate how GSK-3 beta affects the structural plasticity of dendritic spines. Following visualization of dendritic spines with DiI dye, we found that increasing GSK-3 beta activity increased the number of thin spines, whereas lacking GSK-3 beta increased the number of stubby spines in the dentate gyrus. Under conditions of neuronal excitation, increasing GSK-3 beta activity caused higher activity of extracellularly acting matrix metalloproteinase-9 (MMP-9), and MMP inhibition normalized thin spines in GSK-3 beta overexpressing mice. Administration of the nonspecific GSK-3 beta inhibitor lithium in animals with active MMP-9 and animals lacking MMP-9 revealed that GSK-3 beta and MMP-9 act in concert to control dendritic spine morphology. Altogether, our data demonstrate that the dysregulation of GSK-3 beta activity has dramatic consequences on dendritic spine morphology, implicating MMP-9 as a mediator of GSK-3 beta-induced synaptic alterations.