Mouse Model Of MECP2 Duplication Syndrome Research Articles

MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function.

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.

Exploration of group II metabotropic glutamate receptor modulation in mouse models of Rett syndrome and MECP2 Duplication syndrome

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) have opposing molecular origins in relation to expression and function of the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2). Several clinical and preclinical phenotypes, however, are shared between these disorders. Modulation of MeCP2 levels has recently emerged as a potential treatment option for both of these diseases. However, toxicity concerns remain with these approaches. Here, we focus on pharmacologically modulating the group II metabotropic glutamate receptors (mGlu), mGlu2 and mGlu3, which are two downstream targets of MeCP2 that are bidirectionally affected in expression in RTT patients and mice (Mecp2Null/+) versus an MDS mouse model (MECP2Tg1/o). Mecp2Null/+ and MECP2Tg1/o animals also exhibit contrasting phenotypes in trace fear acquisition, a form of temporal associative learning and memory, with trace fear deficiency observed in Mecp2Null/+ mice and abnormally enhanced trace fear acquisition in MECP2Tg1/o animals. In Mecp2Null/+ mice, treatment with the mGlu2/3 agonist LY379268 reverses the deficit in trace fear acquisition, and mGlu2/3 antagonism with LY341495 normalizes the abnormal trace fear learning and memory phenotype in MECP2Tg1/o mice. Altogether, these data highlight the role of group II mGlu receptors in RTT and MDS and demonstrate that both mGlu2 and mGlu3 may be potential therapeutic targets for these disorders.

Antisense oligonucleotide therapy in a humanized mouse model of MECP2 duplication syndrome.

Many intellectual disability disorders are due to copy number variations, and, to date, there have been no treatment options tested for this class of diseases. MECP2 duplication syndrome (MDS) is one of the most common genomic rearrangements in males and results from duplications spanning the methyl-CpG binding protein 2 (MECP2) gene locus. We previously showed that antisense oligonucleotide (ASO) therapy can reduce MeCP2 protein amount in an MDS mouse model and reverse its disease features. This MDS mouse model, however, carried one transgenic human allele and one mouse allele, with the latter being protected from human-specific MECP2-ASO targeting. Because MeCP2 is a dosage-sensitive protein, the ASO must be titrated such that the amount of MeCP2 is not reduced too far, which would cause Rett syndrome. Therefore, we generated an "MECP2 humanized" MDS model that carries two human MECP2 alleles and no mouse endogenous allele. Intracerebroventricular injection of the MECP2-ASO efficiently down-regulated MeCP2 expression throughout the brain in these mice. Moreover, MECP2-ASO mitigated several behavioral deficits and restored expression of selected MeCP2-regulated genes in a dose-dependent manner without any toxicity. Central nervous system administration of MECP2-ASO is therefore well tolerated and beneficial in this mouse model and provides a translatable approach that could be feasible for treating MDS.

Excessive Formation and Stabilization of Dendritic Spine Clusters in the MECP2-Duplication Syndrome Mouse Model of Autism.

Autism-associated genetic mutations may perturb the balance between stability and plasticity of synaptic connections in the brain. Here, we report an increase in the formation and stabilization of dendritic spines in the cerebral cortex of the mouse model of MECP2-duplication syndrome, a high-penetrance form of syndromic autism. Increased stabilization is mediated entirely by spines that form cooperatively in 10-μm clusters and is observable across multiple cortical areas both spontaneously and following motor training. Excessive stability of dendritic spine clusters could contribute to behavioral rigidity and other phenotypes in syndromic autism.

Contextual Fear Extinction Induces Hippocampal Metaplasticity Mediated by Metabotropic Glutamate Receptor 5.

Dysregulated fear memory can lead to a broad spectrum of anxiety disorders. The brain systems underlying fear memory are manifold, with the hippocampus being prominently involved by housing fear-related spatial memories as engrams, which are created and stored through neural changes such as synaptic plasticity. Although metabotropic glutamate (mGlu) receptors contribute significantly to both fear behavior and hippocampal synaptic plasticity, the relationship between these two phenomena has not been fully elucidated. Here, we report that contextual fear extinction induces a novel form of metaplasticity mediated by mGlu5 at the hippocampal SC-CA1 synapse. Further, blockade of mGlu5 prevents both contextual fear extinction and expression of this metaplasticity. This form of metaplasticity was absent in a mouse model of MECP2-duplication syndrome, corresponding to a complete deficit in extinction learning. These findings suggest that mGlu5-dependent metaplasticity within the hippocampus may play a critical role in extinction of contextual fear.