Brain Development

Autism-Risk Gene Rewires the Brain in a Way That Disrupts Learning and Language Acquisition

Source: 
Medical News Today
Date Published: 
November 3, 2010
Abstract: 

Researchers at UCLA have discovered how an autism-risk gene rewires the brain, which could pave the way for treatments aimed at rebalancing brain circuits during early development. Dr. Geschwind and team examined the variations in brain function and connectivity resulting from two forms of the CNTNAP2 gene - one form of the gene increases the risk of autism. The researchers suspected that CNTNAP2 might have an important impact on brain activity. They used fMRI (functional magnetic resonance imaging) to scan 32 children's brains while they were performing tasks related to learning. Only 16 of them had autism.

The imaging results confirmed their suspicions. All the children with the autism-risk gene showed a disjointed brain, regardless of their diagnosis. Their frontal lobe was over-connected to itself, while connection to the rest of the brain was poor, especially with the back of the brain. There was also a difference between how the left and right sides of the brain connected with each other, depending on which CNTNAP2 version the child carried.

The authors believe their findings could help identify autism risk earlier, and eventually lead to interventions that could enhance connections between the frontal lobe and the left side of the brain.

Link Between Genetic Defect And Brain Changes In Schizophrenia Demonstrated

Source: 
Science Daily
Date Published: 
October 17, 2009
Abstract: 

Researchers at the University of North Carolina at Chapel Hill School of Medicine have found that the 22q11 gene deletion -- a mutation that confers the highest known genetic risk for schizophrenia -- is associated with changes in the development of the brain that ultimately affect how its circuit elements are assembled.

The researchers would now like to figure out how these alterations in the circuitry of the brain affect the behavior of the mouse. They also hope that understanding the "mis-wiring" of the brain in a genetic animal model of schizophrenia would help them understand the causes of the disease in the general population

Experts Summarize the State of Research in Autism Spectrum Disorder

Source: 
Science Daily
Date Published: 
October 14, 2009
Abstract: 

Scientific understanding and medical treatments for autism spectrum disorders (ASDs) have advanced significantly over the past several years, but much remains to be done, say experts from the Center for Autism Research at The Children's Hospital of Philadelphia who recently published a scientific review of the field.

Seaside Therapeutics Secures $30 Million Financing

Source: 
Reuters
Date Published: 
September 17, 2009
Abstract: 

Seaside Therapeutics LLC today announced that it has secured $30 million in financing from a private, family investment firm which is committed to advancing research in the field of autism and Fragile X Syndrome.

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.

Researchers identify how PCBs may alter in utero, neonatal brain development

Source: 
PLoS-Biology, Pessah, et al
Date Published: 
April 2009
Year Published: 
2009

In three new studies — including one appearing in the Public Library of Science - Biology (PLoS - Biology) — UC Davis researchers provide compelling evidence of how low levels of polychlorinated biphenyls (PCBs) alter the way brain cells develop.

The findings could explain at last — some 30 years after the toxic chemicals were banned in the United States — the associations between exposure of the developing nervous system to PCBs and behavioral deficits in children.

 

Autism: Maternally derived antibodies specific for fetal brain proteins

Source: 
Neurotoxicology, Braunschweig, Ashwood, et al
Date Published: 
2008
Year Published: 
2008

Autism is a profound disorder of neurodevelopment with poorly understood biological origins. A potential role for maternal autoantibodies in the etiology of some cases of autism has been proposed in previous studies To investigate this hypothesis, maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73kDa and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands correlated with a diagnosis of behavioral regression in the child when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09 - 15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.

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.