Synaptic plasticity and signaling in rett syndrome

Sala, Grazia Della; Pizzorusso, Tommaso

doi:10.1002/dneu.22114

Cited by 31 publications

(16 citation statements)

References 174 publications

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“…Although the activity-dependent release of MMP-9 is implicated in morphological plasticity of mature circuits (Dziembowska et al , 2012), we propose that events occurring early in postnatal development strongly impact the phenotype of MMP-9 −/− mouse brain throughout life. Neurons with shorter dendrites and fewer branches, similar to what we observe in MMP-9 −/− mice, are observed in several developmental neurological disorders including Rett syndrome, fragile X mental retardation, schizophrenia and autism (Braun & Segal, 2000; Shen et al , 2008; Fujita et al , 2010; Janusz et al , 2013; Cheng et al , 2014; Della Sala & Pizzorusso, 2014). Intriguingly, these disorders are also characterized by enhanced neuronal excitability and increased frequency of epilepsy (Canitano, 2007; Guerrini & Parrini, 2012; Kidd et al , 2014; Najjar & Pearlman, 2015).…”

Section: Discussionsupporting

confidence: 82%

Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

et al. 2015

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In early postnatal development, naturally occurring cell death, dendritic outgrowth and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here we demonstrate that deletion of the extracellular proteinase MMP-9 affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons, but decreases dendritic length and complexity while dendritic spine density is unchanged. Parallel changes in neuronal morphology are observed in primary visual cortex, and persist into adulthood. Individual CA1 neurons in MMP-9 −/− mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significant increases spontaneous neuronal activity in awake MMP-9 −/− mice and enhances response to acute challenge by the excitotoxin kainate. Thus MMP-9-dependent proteolysis regulates several aspects of circuit maturation to constrain excitability throughout life.

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Section: Discussionsupporting

confidence: 82%

Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

et al. 2015

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“…However, the current study was conducted in anesthetized animals; future experiments are needed to determine if these same findings are observed in awake animals. Many previous studies have documented GABAergic interneuron and LTP deficits in Rett syndrome, which may be the mechanism responsible for our finding of both hyper and hypoexcitable responses depending on the speed and intensity of the sounds (Chao et al, 2010; Della Sala and Pizzorusso, 2014; Goffin et al, 2014; Medrihan et al, 2008). …”

Section: Discussionmentioning

confidence: 51%

Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome

Engineer

Rahebi

Borland

et al. 2015

Neurobiology of Disease

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Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal. In this study, we used the novel rat Mecp2 knockout model of Rett syndrome to document the neural and behavioral processing of speech sounds. We hypothesized that both speech discrimination ability and the neural response to speech sounds would be impaired in Mecp2 rats. We expected that extensive speech training would improve speech discrimination ability and the cortical response to speech sounds. Our results reveal that speech responses across all four auditory cortex fields of Mecp2 rats were hyperexcitable, responded slower, and were less able to follow rapidly presented sounds. While Mecp2 rats could accurately perform consonant and vowel discrimination tasks in quiet, they were significantly impaired at speech sound discrimination in background noise. Extensive speech training improved discrimination ability. Training shifted cortical responses in both Mecp2 and control rats to favor the onset of speech sounds. While training increased the response to low frequency sounds in control rats, the opposite occurred in Mecp2 rats. Although neural coding and plasticity are abnormal in the rat model of Rett syndrome, extensive therapy appears to be effective. These findings may help to explain some aspects of communication deficits in Rett syndrome and suggest that extensive rehabilitation therapy might prove beneficial.

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“…Overexpression of BDNF appears to restore the dendritic defects in Mecp2 -null condition suggesting a molecular mechanism regulated by MECP2 to maintain the structural stability of neurons (Zhou et al, 2006; Larimore et al, 2009; Gao et al, 2015). Synaptic plasticity is also regulated by the expression or the phosphorylation of MECP2 (Collins et al, 2004; Dani et al, 2005; Asaka et al, 2006; Moretti et al, 2006; Chao et al, 2007; Zhang et al, 2008; Li et al, 2011; Noutel et al, 2011; Blackman et al, 2012; Na et al, 2012, 2013; Qiu et al, 2012; Zhong et al, 2012; Della Sala and Pizzorusso, 2014; Deng et al, 2014; De Filippis et al, 2015). Whether a similar mechanism to Rett or MECP2 duplication syndromes is altered in ASD individuals with MECP2 mutations needs to be further evaluated.…”

Section: Specific Syndromic Disorder Related Genesmentioning

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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Synaptic plasticity and signaling in rett syndrome

Cited by 31 publications

References 174 publications

Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability

Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome

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

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