Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder

Fuchs, Claudia; Rimondini, Roberto; Viggiano, Rocchina; Trazzi, Stefania; Franceschi, Marianna De; Bartesaghi, Renata; Ciani, Elisabetta

doi:10.1016/j.nbd.2015.06.018

Cited by 59 publications

(101 citation statements)

References 30 publications

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“…This observation was surprising, because two previous studies reported that both PSD-95 and VGluT1 levels are reduced in CDKL5 deficient mice (Ricciardi et al, 2012; Fuchs et al, 2015). It is worth noting that in Ricciardi et al (2012) CDKL5 was manipulated by in utero electroporation, resulting in a downregulation of CDKL5 protein rather than a complete loss.…”

Section: Discussionmentioning

confidence: 94%

“…This hypothesis is also supported by findings from Chen et al (2010), showing a postnatal migration delay of pyramidal cortical neurons in rats silenced for CDKL5. In Fuchs et al (2015), the reduction of VGluT1 was revealed in the molecular layer of the hippocampal dentate gyrus, a brain structure that markedly differs from the visual cortex. It is thus plausible that Cdkl5 deletion may result in region-specific abnormalities of synaptic connectivity.…”

Section: Discussionmentioning

confidence: 97%

“…We showed that Cdkl5 KOs exhibit behavioral abnormalities that resemble RTT-like phenotypes, such as hind-limb clasping, hypoactivity and visual attention/acuity deficits (Amendola et al, 2014). 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).…”

Section: Introductionmentioning

confidence: 99%

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

Pizzo

Gurgone

Castroflorio

et al. 2016

Front. Cell. Neurosci.

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Cyclin-dependent kinase-like 5 (CDKL5) mutations are found in severe neurodevelopmental disorders, including the Hanefeld variant of Rett syndrome (RTT; CDKL5 disorder). CDKL5 loss-of-function murine models recapitulate pathological signs of the human disease, such as visual attention deficits and reduced visual acuity. Here we investigated the cellular and synaptic substrates of visual defects by studying the organization of the primary visual cortex (V1) of Cdkl5−/y mice. We found a severe reduction of c-Fos expression in V1 of Cdkl5−/y mutants, suggesting circuit hypoactivity. Glutamatergic presynaptic structures were increased, but postsynaptic PSD-95 and Homer were significantly downregulated in CDKL5 mutants. Interneurons expressing parvalbumin, but not other types of interneuron, had a higher density in mutant V1, and were hyperconnected with pyramidal neurons. Finally, the developmental trajectory of pavalbumin-containing cells was also affected in Cdkl5−/y mice, as revealed by fainter appearance perineuronal nets at the closure of the critical period (CP). The present data reveal an overall disruption of V1 cellular and synaptic organization that may cause a shift in the excitation/inhibition balance likely to underlie the visual deficits characteristic of CDKL5 disorder. Moreover, ablation of CDKL5 is likely to tamper with the mechanisms underlying experience-dependent refinement of cortical circuits during the CP of development.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

Pizzo

Gurgone

Castroflorio

et al. 2016

Front. Cell. Neurosci.

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“…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).…”

Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

“…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.…”

Section: Perspectivesmentioning

confidence: 99%

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

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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Autism Spectrum Disorders

Anderson

2018

Developmental Neuropathology

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Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder

Cited by 59 publications

References 30 publications

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

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

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

Autism Spectrum Disorders

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