Sensory over-responsivity and aberrant plasticity in cerebellar cortex in a mouse model of syndromic autism

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.

Download Full-text

Substantially thinner internal granular layer and reduced molecular layer surface in the cerebellar cortex of the Tc1 mouse model of down syndrome – a comprehensive morphometric analysis with active staining contrast-enhanced MRI

NeuroImage ◽

10.1016/j.neuroimage.2020.117271 ◽

2020 ◽

Vol 223 ◽

pp. 117271

Author(s):

Da Ma ◽

Manuel J. Cardoso ◽

Maria A. Zuluaga ◽

Marc Modat ◽

Nick M. Powell ◽

...

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Cerebellar Cortex ◽

Morphometric Analysis ◽

Granular Layer ◽

Molecular Layer ◽

Layer Surface ◽

Contrast Enhanced ◽

Internal Granular Layer ◽

Contrast Enhanced Mri

Download Full-text

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.

Download Full-text

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

10.1101/186239 ◽

2017 ◽

Author(s):

Ryan T. Ash ◽

Paul G. Fahey ◽

Jiyoung Park ◽

Huda Y. Zoghbi ◽

Stelios M. Smirnakis

Keyword(s):

Motor Learning ◽

Mouse Model ◽

Dendritic Spine ◽

Pyramidal Neuron ◽

Structural Plasticity ◽

Autism Spectrum ◽

Wild Type ◽

Syndromic Autism ◽

Mecp2 Duplication Syndrome ◽

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.

Download Full-text

Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

Download Full-text