The short-time structural plasticity of dendritic spines is altered in a model of Rett syndrome

Landi, Silvia; Putignano, Elena; Boggio, Elena; Giustetto, Maurizio; Pizzorusso, Tommaso; Ratto, Gian Michele

doi:10.1038/srep00045

Cited by 76 publications

(63 citation statements)

References 57 publications

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“…Prominent among these are compounds that modulate synaptic development and function, such as insulin‐like growth factor 1 (IGF‐1), which shares many features with brain‐derived neurotrophic factor (BDNF), including activation of the AKT signaling pathway 17, 18. Evaluation of IGF‐1, and its active N‐terminus peptide, in MECP2 mouse models, has rescued many RTT‐like symptoms 19, 20, 21. These experimental findings have led to two phase 2 trials with the IGF‐1 peptide analog trofinetide (NCT01703533 and NCT02715115) and one phase 1 trial with recombinant human IGF‐1 (rhIGF‐1) also termed mecasermin 22…”

Section: Introductionmentioning

confidence: 99%

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

O’Leary

Kaufmann

Barnes

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo measure the efficacy of mecasermin (recombinant human insulin‐like growth factor 1, rhIGF‐1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double‐blind crossover study design.MethodsThirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF‐1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28‐week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory‐ and electroencephalography (EEG)‐based biomarkers were also analyzed.ResultsThere were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication.InterpretationAs in the phase 1 trial, rhIGF‐1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

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Section: Introductionmentioning

confidence: 99%

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

O’Leary

Kaufmann

Barnes

et al. 2018

Ann Clin Transl Neurol

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“…Spine motility was assessed by imaging a segment of the apical tuft of L5 pyramidal neurons every 5 min for at least 1 h and measuring the spine length at each time point 27 . Motility was measured by computing the rate of change of spine length during each 5 min period.…”

Section: Resultsmentioning

confidence: 99%

“…Images were analyzed with ImageJ 27 . The optical sections of each stack were aligned to compensate for mechanical movements with a custom macro in ImageJ.…”

Section: Methodsmentioning

confidence: 99%

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

et al. 2013

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Brain cells are immersed in a complex structure forming the extracellular matrix. The composition of the matrix gradually matures during postnatal development, as the brain circuitry reaches its adult form. The fully developed extracellular environment stabilizes neuronal connectivity and decreases cortical plasticity as highlighted by the demonstration that treatments degrading the matrix are able to restore synaptic plasticity in the adult brain. The mechanisms through which the matrix inhibits cortical plasticity are not fully clarified. Here we show that a prominent component of the matrix, chondroitin sulfate proteoglycans (CSPGs), restrains morphological changes of dendritic spines in the visual cortex of adult mice. By means of in vivo and in vitro two-photon imaging and electrophysiology, we find that after enzymatic digestion of CSPGs, cortical spines become more motile and express a larger degree of structural and functional plasticity.

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“…Furthermore, administration of IGF-1 restores dendritic spine dynamics in Mecp2-deficient mice (12). The most compelling data supporting IGF-1 as a treatment for RTT come from two studies demonstrating that systemic administration of either full length IGF-1 or its active peptide fragment reverses, at least partially, many RTT-relevant features in Mecp2-deficient mice (13,14).…”

Section: Significancementioning

confidence: 96%

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Khwaja

Barnes

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

174

203

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Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulinlike growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

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The short-time structural plasticity of dendritic spines is altered in a model of Rett syndrome

Cited by 76 publications

References 57 publications

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

Placebo‐controlled crossover assessment of mecasermin for the treatment of Rett syndrome

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

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