Synapse

Findings on Cell Interactions Published by U. Iowa Biologists

Source: 
Medical News Today
Date Published: 
August 5, 2010
Abstract: 

Two University of Iowa biologists have published a paper on how cells make specific interactions during development -- in the hope of one day learning more about human developmental disorders.

Mutations in the SHANK2 Synaptic Scaffolding Gene in Autism Spectrum

Source: 
Nature Genetics, Berkel et al
Date Published: 
June 2010
Year Published: 
2010

Using microarrays, the department of molecular human genetics in Heidelberg, Germany identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation. DNA sequencing of SHANK2 in 396 individuals with ASD, 184 individuals with mental retardation and 659 unaffected individuals (controls) revealed additional variants that were specific to ASD and mental retardation cases, including a de novo nonsense mutation and seven rare inherited changes. Their findings further link common genes between ASD and intellectual disability.

Schizophrenia Shares Genetic Links with Autism, Genome Study Shows

Source: 
Scientific American
Date Published: 
May 10, 2010
Abstract: 

Schizophrenia involves some of the same genetic variations as autism and attention deficit disorders, a new whole-genome study has confirmed. In an effort to assess some of the common genetic variations that might underpin this fairly common but thorny mental illness, researchers sequenced DNA from 1,735 adults with schizophrenia and 3,485 healthy adults. Across the patients that had the disease, the researchers found many frequent variations related to copying or deleting genes, known as copy-number variations.

Brain Development Steered By Newly Discovered RNA

Source: 
Medical News Today
Date Published: 
April 16, 2010
Abstract: 

New research from the lab of Michael Greenberg, Nathan Marsh Pusey professor and chair of neurobiology at HMS, in collaboration with bioinformatics specialist and neuroscientist Gabriel Kreiman, assistant professor of ophthalmology at Children's Hospital, Boston, has found that a particular set of RNA molecules widely considered to be no more than a genomic oddity are actually major players in brain development - and are essential for regulating the process by which neurons absorb the outside world into their genetic machinery.

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

Source: 
PLOS Genetics, Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, et al.
Date Published: 
June 2009
Year Published: 
2009

The study identified 27 different genetic regions where rare copy number variations - missing or extra copies of DNA segments - were found in the genes of children with autism spectrum disorders, but not in the healthy controls. The researchers, including geneticists from the University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia (CHOP) compared genetic samples of 3,832 individuals from 912 families with multiple autistic children against genetic samples of 1,070 disease-free children. Besides the identification of 27 regions harboring rare variants in children with ASDs, the study also uncovered two novel genes where variations were found, BZRAP1 and MDGA2 - thought to be important in synaptic function and neurological development, respectively. Interestingly, key variants on these genes were passed down in some, but not all, of the affected individuals in families.

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.

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.

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.

Identifying autism Loci and Genes by Tracing Recent Shared Ancestry

Source: 
Science, Morrow, Yoo, et al
Date Published: 
2008

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.