Animal Models

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Source: 
PNAS, Sur, Tropea, Giacometti, et al.
Date Published: 
February 2009
Year Published: 
2009

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Molecular Cytogenetic Analysis and Resequencing of Contactin Associate Protein-Like 2 in Autism Spectrum Disorders

Source: 
American Journal of Human Genetics, Bakkaloglu, O’Roak, et al
Date Published: 
2008
Year Published: 
2008

Autism spectrum disorders (ASD) are a group of related neurodevelopmental syndromes with complex genetic etiology. We identified a de novo chromosome 7q inversion disrupting Autism susceptibility candidate 2 (AUTS2) and Contactin Associated Protein-Like 2 (CNTNAP2) in a child with cognitive and social delay. We focused our initial analysis on CNTNAP2 based on our demonstration of disruption of Contactin 4 (CNTN4) in a patient with ASD; the recent finding of rare homozygous mutations in CNTNAP2 leading to intractable seizures and autism; and in situ and biochemical analyses reported herein that confirm expression in relevant brain regions and demonstrate the presence of CNTNAP2 in the synaptic plasma membrane fraction of rat forebrain lysates. We comprehensively resequenced CNTNAP2 in 635 patients and 942 controls. Among patients, we identified a total of 27 nonsynonymous changes; 13 were rare and unique to patients and 8 of these were predicted to be deleterious by bioinformatic approaches and/or altered residues conserved across all species. One variant at a highly conserved position, I869T, was inherited by four affected children in three unrelated families, but was not found in 4010 control chromosomes (p = 0.014). Overall, this resequencing data demonstrated a modest nonsignificant increase in the burden of rare variants in cases versus controls. Nonetheless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.

Fragile X: Translation in Action

Source: 
Neuropshcyopharmacology, Bear, Dolen et al
Date Published: 
2008

Fragile X is a synapsopathy--a disorder of synaptic function and plasticity. Recent studies using mouse models of the disease suggest that the critical defect is altered regulation of synaptic protein synthesis. Various strategies to restore balanced synaptic protein synthesis have been remarkably successful in correcting widely varied mutant phenotypes in mice. Insights gained by the study of synaptic plasticity in animal models of fragile X have suggested novel therapeutic approaches, not only for human fragile X but also for autism and mental retardation of unknown etiology.

MeCP2, A Key Contributor to Neurological Disease, Activates and Represses Transcription

Source: 
Science, Chahrour, Jung et al
Date Published: 
2008

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (approximately 85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.

Tuberous Sclerosis Complex Proteins Control Axon Formation

Source: 
Genes Development, Choi, DiNardo, et al
Date Published: 
2008
Year Published: 
2008

Axon formation is fundamental for brain development and function. TSC1 and TSC2 are two genes, mutations in which cause tuberous sclerosis complex (TSC), a disease characterized by tumor predisposition and neurological abnormalities including epilepsy, mental retardation, and autism. Here we show that Tsc1 and Tsc2 have critical functions in mammalian axon formation and growth. Overexpression of Tsc1/Tsc2 suppresses axon formation, whereas a lack of Tsc1 or Tsc2 function induces ectopic axons in vitro and in the mouse brain. Tsc2 is phosphorylated and inhibited in the axon but not dendrites. Inactivation of Tsc1/Tsc2 promotes axonal growth, at least in part, via up-regulation of neuronal polarity SAD kinase, which is also elevated in cortical tubers of a TSC patient. Our results reveal key roles of TSC1/TSC2 in neuronal polarity, suggest a common pathway regulating polarization/growth in neurons and cell size in other tissues, and have implications for the understanding of the pathogenesis of TSC and associated neurological disorders and for axonal regeneration.

Reversal of Learning Deficits in a Ts2+/- Mouse Model of Tuberous Sclerosis

Source: 
Nature Medicine, Ehninger, Han, et al
Date Published: 
2008
Year Published: 
2008

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.

Stereotypes and Hyperactivity in Rhesus Monkeys Exposed to IgG from Mothers of Children with Autism

Source: 
Brain Behavior Immunology, Martin, Ashwood, Braunschweig, Cabanlit, Van de Water, Amaral
Date Published: 
2008

One proposed cause of ASD is exposure of the fetal brain to maternal autoantibodies during pregnancy [Dalton, P., Deacon, R., Blamire, A., Pike, M., McKinlay, I., Stein, J., Styles, P., Vincent, A., 2003. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537]. To provide evidence for this hypothesis, four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Monkeys were observed in a variety of behavioral paradigms involving unique social situations. Behaviors were scored by trained observers and overall activity was monitored with actimeters. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls. Treatment with IgG purified from mothers of typically developing children did not induce stereotypical or hyperactive behaviors. These findings support the potential for an autoimmune etiology in a subgroup of patients with neurodevelopmental disorders. This research raises the prospect of prenatal evaluation for neurodevelopmental risk factors and the potential for preventative therapeutics.

Antibodies Against Fetal Brain in Sera of Mothers with Autistic Children

Source: 
Journal of Neuroimmunology, Singer, Morris, Gause, Gillin, Crawford, Zimmerman

Serum antibodies in 100 mothers of children with autistic disorder (MCAD) were compared to 100 age-matched mothers with unaffected children (MUC) using as antigenic substrates human and rodent fetal and adult brain tissues, GFAP, and MBP. MCAD had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue. The density of bands was greater in fetal brain at 61 kDa. MCAD plus developmental regression had greater reactivity against human fetal brain at 36 and 39 kDa. Data support a possible complex association between genetic/metabolic/environmental factors and the placental transfer of maternal antibodies in autism.