Increased axonal bouton stability during learning in the mouse model of MECP2 duplication syndrome

ABSTRACTMECP2-duplication syndrome is an X-linked form of syndromic autism caused by genomic duplication of the region encoding Methyl-CpG-binding protein 2. Mice overexpressing MECP2 demonstrate altered patterns of learning and memory, including enhanced motor learning. Previous work associated this enhanced motor learning to abnormally increased stability of dendritic spine clusters formed in the apical tuft of corticospinal, area M1, neurons during rotarod training. In the current study, we measure the structural plasticity of axonal boutons in Layer 5 (L5) pyramidal neuron projections to layer 1 of area M1 during motor learning. In wild-type mice we find that during rotarod training, bouton formation rate changes minimally, if at all, while bouton elimination rate doubles. Notably, the observed upregulation in bouton elimination with learning is absent in MECP2-duplication mice. This result provides further evidence of imbalance between structural stability and plasticity in this form of syndromic autism. Furthermore, the observation that axonal bouton elimination doubles with motor learning in wild-type animals contrasts with the increase of dendritic spine consolidation observed in corticospinal neurons at the same layer. This dissociation suggests that different area M1 microcircuits may manifest different patterns of structural synaptic plasticity during motor learning.SIGNIFICANCE STATEMENTAbnormal balance between synaptic stability and plasticity is a feature of several autism spectrum disorders, often corroborated by in vivo studies of dendritic spine turnover. Here we provide the first evidence that abnormally increased stability of axonal boutons, the presynaptic component of excitatory synapses, occurs during motor learning in the MECP2 duplication syndrome mouse model of autism. In contrast, in normal controls, axonal bouton elimination in L5 pyramidal neuron projections to layer 1 of area M1 doubles with motor learning. The fact that axonal projection boutons get eliminated, while corticospinal dendritic spines get consolidated with motor learning in layer 1 of area M1, suggests that structural plasticity manifestations differ across different M1 microcircuits.

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Excessive ERK-dependent synaptic clustering drives enhanced motor learning in the MECP2 duplication syndrome mouse model of autism

10.1101/100875 ◽

2017 ◽

Cited By ~ 2

Author(s):

Ryan Thomas Ash ◽

Shelly Alexandra Buffington ◽

Jiyoung Park ◽

Mauro Costa-Mattioli ◽

Huda Yaya Zoghbi ◽

...

Keyword(s):

Motor Learning ◽

Mouse Model ◽

Learning And Memory ◽

Erk Signaling ◽

Learning Abilities ◽

Spine Stabilization ◽

Syndromic Autism ◽

Mecp2 Duplication Syndrome ◽

Repetitive Motor ◽

Duplication Syndrome

AbstractAutism-associated genetic mutations may produce altered learning abilities by perturbing the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the stabilization of dendritic spines formed during repetitive motor learning in the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. This increased stabilization is mediated entirely by spines that form cooperatively in clusters. The number of clusters formed and stabilized predicts the mutant’s enhanced motor learning and memory phenotype, reminiscent of savant-like behaviors occasionally associated with autism.The ERK signaling pathway, which promotes cooperative plasticity between spines, was found to be hyperactive in MECP2-duplication motor cortex specifically after training. Inhibition of ERK signaling normalizes clustered spine stabilization and rescues motor learning behavior in mutants. We conclude that learning-associated dendritic spine clustering stabilized by hyperactive ERK signaling drives abnormal motor learning and memory consolidation in this model of syndromic autism.

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Excessive formation and stabilization of dendritic spine clusters in the MECP2 duplication syndrome mouse model of autism

eNeuro ◽

10.1523/eneuro.0282-20.2020 ◽

2020 ◽

pp. ENEURO.0282-20.2020

Author(s):

Ryan Thomas Ash ◽

Jiyoung Park ◽

Bernhard Suter ◽

Huda Yaya Zoghbi ◽

Stelios Manolis Smirnakis

Keyword(s):

Mouse Model ◽

Dendritic Spine ◽

Mecp2 Duplication Syndrome ◽

Duplication Syndrome

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Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith–Magenis syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1806796115 ◽

2018 ◽

Vol 115 (42) ◽

pp. 10744-10749 ◽

Cited By ~ 9

Author(s):

Wei-Hsiang Huang ◽

David C. Wang ◽

William E. Allen ◽

Matthew Klope ◽

Hailan Hu ◽

...

Keyword(s):

Social Interaction ◽

Mouse Model ◽

Behavioral Problems ◽

Autism Spectrum ◽

Inhibitory Neurons ◽

Critical Window ◽

Genetic Mouse Model ◽

Expression Of Genes ◽

Syndromic Autism ◽

Level 3

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

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4225 Evaluation of Neurotransmitters in Channelopathy-Related Epilepsy

Journal of Clinical and Translational Science ◽

10.1017/cts.2020.298 ◽

2020 ◽

Vol 4 (s1) ◽

pp. 95-95

Author(s):

Sunita N Misra ◽

Theresa M. Czech ◽

Jennifer A. Kearney

Keyword(s):

Mouse Model ◽

Chart Review ◽

Retrospective Chart Review ◽

Brain Regions ◽

Autism Spectrum ◽

Wild Type ◽

Voltage Gated Sodium Channels ◽

Study Population ◽

Genotype A

OBJECTIVES/GOALS: Variants in voltage-gated sodium channels (VGSC) are a common cause of severe early onset epilepsy. Changes in CSF neurotransmitters (NT) were identified in 2 cases of VGSC-related epilepsy. Here we investigate NT changes in patients and a novel mouse model of VGSC-related epilepsy. METHODS/STUDY POPULATION: We conducted a single site IRB approved retrospective chart review of patients with VGSC-related epilepsy who underwent CSF NT testing for diagnostic purposes. In parallel, we examined NT levels from the brains of wild-type (WT) and a novel VGSC-related epilepsy mouse model after obtaining IACUC approval. We rapidly isolated forebrain, cortex, striatum, and brainstem from 5-6 animals per sex and genotype. A combination of HPLC with electrochemical detection and mass spectrometry were used to quantify NT levels from brain samples. RESULTS/ANTICIPATED RESULTS: We identified 10 patients with VGSC-related epilepsy who received CSF NT testing. Two of these patients had abnormal NT results including changes to dopamine (DA) or serotonin (5-HT) metabolites. We analyzed NT levels from four brain regions from male and female WT and VGSC-related epilepsy mice. We anticipate that most of the NT levels will be similar to WT, however subtle changes in the DA or 5-HT metabolites may be seen in VGSC-related epilepsy. DISCUSSION/SIGNIFICANCE OF IMPACT: Patients with VGSC-related epilepsy often have autism spectrum disorder, sleep, and movement disorders. Understanding the role of aberrant NT levels in VGSC-related epilepsy may provide additional therapeutic targets that address common neuropsychological comorbidities as well as seizures.

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Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model

Neural Plasticity ◽

10.1155/2019/4893103 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Musaad A. Alshammari ◽

Mohammad R. Khan ◽

Fawaz Alasmari ◽

Abdulaziz O. Alshehri ◽

Rizwan Ali ◽

...

Keyword(s):

Mouse Model ◽

Western Blot ◽

Neuronal Excitability ◽

Autism Spectrum ◽

Wild Type ◽

Western Blot Assay ◽

Critical Determinant ◽

Molecular Features ◽

Voltage Gated Sodium Channels ◽

Wild Type Control

The axon initial segment (AIS), the site of action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that appropriate recruitment of the AIS macrocomplex is essential for synchronized firing. However, disruption of the AIS structure is linked to the etiology of multiple disorders, including autism spectrum disorder (ASD), a condition characterized by deficits in social communication, stereotyped behaviors, and very limited interests. To date, a complete understanding of the molecular components that underlie the AIS in ASD has remained elusive. In this research, we examined the AIS structure in a BTBR T+Itpr3tf/J mouse model (BTBR), a valid model that exhibits behavioral, electrical, and molecular features of autism, and compared this to the C57BL/6J wild-type control mouse. Using Western blot studies and high-resolution confocal microscopy in the prefrontal frontal cortex (PFC), our data indicate disrupted expression of different isoforms of the voltage-gated sodium channels (NaV) at the AIS, whereas other components of AIS such as ankyrin-G and fibroblast growth factor 14 (FGF14) and contactin-associated protein 1 (Caspr) in BTBR were comparable to those in wild-type control mice. A Western blot assay showed that BTBR mice exhibited a marked increase in different sodium channel isoforms in the PFC compared to wild-type mice. Our results provide potential evidence for previously undescribed mechanisms that may play a role in the pathogenesis of autistic-like phenotypes in BTBR mice.

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