Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1

Abstract

Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by IGF-1, Biological Psychiatry, http: //dx.doi.org/10.1016/j.biopsych. 2015.08.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex

“…Both PSD-95 and Homer clusters were significantly reduced in cortical layers of Cdkl5 KO mice compared with the control littermates. This is consistent with previous findings showing that CDKL5 plays a critical role in orchestrating the molecular composition, stabilization and functionality of excitatory postsynapses and that its absence severely affects the morphology and dynamics of dendritic spines, possibly destabilizing PSD-95-NGL-1 interaction (Ricciardi et al, 2012; Della Sala et al, 2016). Intriguingly, alteration of excitatory transmission was reported recently by studies conducted on neurons derived from CDKL5 mutated human iPS cells (Ricciardi et al, 2012).…”

“…These defects are associated with neuroanatomical alterations, such as a significant reduction of the thickness of somatosensory cortex and hippocampus, and a decreased length and complexity of dendritic arborization of pyramidal neurons (Amendola et al, 2014; Fuchs et al, 2015). Cdkl5-KO mice also present severe deficits in the organization and stability of dendritic spines, as well as in the density of PSD-95 dendritic clusters and synaptic long-term potentiation (Della Sala et al, 2016). …”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…In the cytosol, CDKL5 postively regulates neurite outgrowth and dendritic arborization via binding with Rac1 (Chen et al, 2010b). With this broad influence on neuronal function, Cdkl5 null mice have several defects ranging from neuronal survival, dendritie maturation, spine stability, synaptic plasticity, and behaviors (Amendola et al, 2014; Fuchs et al, 2014; Della Sala et al, 2016). Treatment of Cdkl5 null mice with insulin-like growth factor 1 (IGF-1) or the glycogen synthase kinase 3β (GSK3β) inhibitor can rescue these defective phenotypes (Della Sala et al, 2016; Fuchs et al, 2015).…”

“…With this broad influence on neuronal function, Cdkl5 null mice have several defects ranging from neuronal survival, dendritie maturation, spine stability, synaptic plasticity, and behaviors (Amendola et al, 2014; Fuchs et al, 2014; Della Sala et al, 2016). Treatment of Cdkl5 null mice with insulin-like growth factor 1 (IGF-1) or the glycogen synthase kinase 3β (GSK3β) inhibitor can rescue these defective phenotypes (Della Sala et al, 2016; Fuchs et al, 2015). Furthermore, CDKL5 has been shown to bind to palmitoylated-PSD-95 and this interaction is important for synaptic targeting of CDKL5 and spine formation (Zhu et al, 2013).…”

“…The alteration of IGF-1/GSK3β pathway is implicated in Pten (Kwon et al, 2006), Cdk5l (Fuchs et al, 2014) or Mecp2 (Itoh et al, 2007) mutant animals. Inhibition of GSK3β or application of IGF-1 can rescue the dendritic phenotype in Cdk5l and Mecp2 mutant mice (Tropea et al, 2009; Fuchs et al, 2015; Della Sala et al, 2016). The mTOR pathway and the GSK3β pathway can be further linked together as they are both regulated by AKT.…”