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

Abstract

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-3β (GSK-3β) has been implicated. Despite much evidence of the involvement of GSK-3β in functional synaptic plasticity, it is unclear how GSK-3β 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-3β in neurons to investigate how GSK-3β affects the structural plasticity of dendritic spines. Following visualization of dendritic spines with DiI dye, we found that increasing GSK-3β activity increased the number of thin spines, whereas lacking GSK-3β increased the number of stubby spines in the dentate gyrus. Under conditions of neuronal excitation, increasing GSK-3β activity caused higher activity of extracellularly acting matrix metalloproteinase-9 (MMP-9), and MMP inhibition normalized thin spines in GSK-3β overexpressing mice. Administration of the nonspecific GSK-3β inhibitor lithium in animals with active MMP-9 and animals lacking MMP-9 revealed that GSK-3β and MMP-9 act in concert to control dendritic spine morphology. Altogether, our data demonstrate that the dysregulation of GSK-3β activity has dramatic consequences on dendritic spine morphology, implicating MMP-9 as a mediator of GSK-3β-induced synaptic alterations.

Protease induced plasticity: matrix metalloproteinase-1 promotes neurostructural changes through activation of protease activated receptor 1

“…PAR1 signaling may contribute to altered dendritic spine density through β-arrestin-mediated activation of GSK-3β 39 . GSK-3β activation through dephosphorylation of serine 9 has been linked to an increase in thin dendritic spines on hippocampal neurons and PAR1 signaling 40 41 . To determine whether GSK-3β activity is increased in the hMMP-1 Tg mice, we tested hippocampal lysates for serine 9 phosphorylated and total GSK-3β levels by ELISA.…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…Finally, cortical pyramidal neurons from a mouse line mutant for the neuronally expressed Wnt/β-catenin pathway activator and DISC1 partner Dixdc1 have reduced dendritic spine and excitatory synapse density correlating with phenotypes in the affective domain (behavioral despair) and social domain (reciprocal social interaction); administration of either lithium or a selective GKS3 inhibitor corrects both the neurodevelopmental and behavioral phenotypes in these animals [343]. This supports that a major neurodevelopmental/neuroplastic target of lithium - and of other psychiatric drugs that either directly or indirectly modulate GSK3 - is the formation, stability, and/or turnover of dendritic spines and glutamatergic synapses [325,344,345]. The same study also provided evidence supporting a “goldilocks principle” for Wnt signaling in these processes at the dendritic spine and synapse, showing that either too much or too little signal pathway activation is similarly deleterious [343].…”

c-Fos and neuronal plasticity: the aftermath of Kaczmarek’s theory

“…MMP-9 mRNA is one of the transcripts that undergoes local synaptic translation to produce the protein that is rapidly released in response to stimulation (Dziembowska et al 2012, Janusz et al 2013, Michaluk et al 2007. Moreover, MMP-9 is an essential regulator of dendritic spine dynamics (Jasinska et al 2016, Kondratiuk et al 2016, Michaluk et al 2011, Szepesi et al 2013, 2014. In addition to its role in brain physiology, MMP-9 was shown to be implicated in aberrant plasticity and contributes to various brain disorders, such as epilepsy, alcoholism, stress, and schizophrenia (Lepeta et al 2017, Pijet et al 2018, Samochowiec et al 2010, Wilczynski et al 2008, Zybura-Broda et al 2016).…”