Maternal stress alters behavior of generations
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Forced separation: Offspring of mothers restrained in a box or compelled to swim in a beaker of cold water show gene expression changes that are passed down to their descendants.
Preventing mothers from nurturing their pups alters social behavior and gene expression in the following three generations of mice, according to research presented 13 April at the Wiring the Brain meeting held outside Dublin, Ireland.
This first clear demonstration of the ways that early trauma marks successive generations suggests a partial explanation for the 'hidden heritability' puzzle in complex neuropsychiatric disorders, including autism.
Genetic analysis turns up only a few risk factors for these complex disorders. Even among those who carry known risk factors, the disorders often manifest differently.
The new study shows that environmental factors can directly alter gene expression, indicating the importance of gene-environment interactions in disorders such as autism and schizophrenia.
The researchers separated female rodents from their pups for up to three hours a day in random 15-minute intervals for two weeks early in postnatal life. Later in life, these pups show social deficits and behaviors reminiscent of both depression and impulsivity in humans.
Genes that modulate anxiety, such as CRFR2, and genes known to be important for epigenetic regulation — including MeCP2, the gene responsible for Rett syndrome — are either over-expressed or under-expressed in three generations of offspring, says lead investigator Isabelle Mansuy, professor of molecular cognition at the University of Zurich Swiss Federal Institute of Technology.
"Molecular analysis shows persistent changes in the expression of several genes in male and female offspring," says Mansuy. She observed the changes in both germ cells and brains of adult offspring.
Social behavior is more severely affected in the males, she says, whereas females are more likely to show behaviors reminiscent of helplessness and depression.
Interestingly, some male offspring do not show behavioral effects themselves, but appear to transmit the epigenetic changes, and associated behaviors, to their daughters.
"The big question is, what are the mechanisms of transmission?" Mansuy says. "To show that methylation is altered in germ cells and is maintained is one thing, but what are the mechanisms that alter methylation in sperm? That is the big biological question."
Stress studies:
Handling female mice while their pups are feeding has previously been shown to increase anxiety in their offspring throughout their lives. This is thought to result from methylation of the receptor gene for oxytocin, a hormone involved in social and maternal bonding and trust.
Studies have found significantly lower levels of oxytocin in the blood of children with autism compared with controls. Epigenetic changes in OXTR, the oxytocin receptor, have also been reported in people with autism.
Mice used in the new study are known to be excellent nurturers of their offspring. This perhaps amplified the level of stress they felt when they were chronically and unpredictably separated from their pups, says Mansuy. During the periods of separation, the mothers were either restrained in a box or compelled to swim in a beaker of cold water, while the pups were left alone in their cages.
Researchers waited until the offspring were 3 months of age — young adulthood in mouse years — and then until the mice reached 1.5 years, a geriatric age in mice, to assess their behavior. Behavioral consequences of maternal deprivation and stress worsen with age, the study found.
Male offspring show more severe social deficits — for example, a lack of interest in new animals introduced into their cages. Females show interest in new cage-mates but fail to recognize animals previously introduced into their cages. Females also show more symptoms of depression. When immersed in a beaker of water, rather than swimming, they tend to give up and float faster than do typical animals.
Both male and female offspring of the stressed mothers are much more impulsive than are typical controls.
Treatment with antidepressants improves social behavior in the animals. Strikingly, so does placing the animals in enriched housing environments with eight to ten same-sex companions, mazes and toys.
Mansuy also found altered methylation in the CpG islands — genomic regions that tend to be located near sites where gene expression is initiated — of approximately 250 genes. Among these genes are CRFR2 — which helps maintain homeostasis in response to stress — and MeCP2. Genes associated with the modulation of synaptic strength are also affected, as is OXTR — although that observation still needs to be confirmed.
Environmental factors are known to increase the risk of developing schizophrenia, notes Andreas Meyer-Lindenberg, director of the Central Institute of Mental Health in Heidelberg, Germany. For example, being born and raised in an urban area is known to raise the risk of developing schizophrenia three-fold.
By contrast, gene-environment interactions are not as well studied in autism, he says, though factors like urbanization and migration may raise the risk (and prevalence) of autism as well.
"Genetic effects are subtle," he says. "[But] these things are sledgehammers."
Comments
This report raises a new question being asked with increasing frequency, what is the answer to the 'missing heritability' puzzle. The 'missing heritability' puzzle may have already been identified but has simply not been recognized.
In his reference book 'Genes and Behavior:Nature-Nurture Interplay Explained', Sir Michael Rutter correctly argues, referencing the work of Kendler, that 'the strong, clear and direct causal relationship implied by the concepts of a 'a gene for' does not exist for psychiatric disorders. Although we may wish it to be true, we do not have and are not likely ever to discover 'genes for' psychiatric illness'. Page 13)
Genetic research over the last two decades have proven this statement to be true. There is no rare chromosomal mutation or common genetic variant which has been found to be specific to autism risk. The same major rare chromosomal single-gene mutations (Fragile X, Tuberous Sclerosis, Rhett Syndrome, Downs Syndrome, 16P11.2 etc) and common genetic variants (COMT, MET, 5P14.1, CNTNAP2, Serotonin Transporter (5-HTT) etc.), that represent autism risk have also been identified as associated with risk for disruption of early brain development and a broad spectrum of neurodevelopmental and neuropsychiatric conditions including autism, schizophrenia, ADHD, bipolar disorder, intellectual disability, depression, social anxiety, developmental delay, childhood language disorders and epilepsy.
Before the publication of his book, Rutter raised the possibility that autism etiology may involve a 'two-hit' mechanism and that there may be separate stimulus of a kind that hasn't been recognized. He explained his notion of a two-hit mechanism in the following brief 4 minute video:
http://www.youtube.com/watch?v=0MVLH4B0tEU&feature=related
A few years later Rutter further expanded on the notion of a two hit mechanism again in his book 'Genes and Behavior: Nature-Nurture Interplay Explained':
“In other words, what is required for autism 'proper' to develop are the susceptibility genes and some other risk factor that could be either genetic or environmental in origin. The implication, if it is a two hit process is that the genes underlying the broader autism phenotype may not be exactly the same as those involved in the transition to the handicapping disorder.” (Page 136)
There is evidence from genetic syndromes and congenital syndromes with an identified medical cause that independent separate (two-hit) mechanisms are involved in autism etiology. The further implications of a two-mechanism is that the primary independent component part is the complex multiple genetic and environmental factors involved in the disruption of early brain development. The secondary component part are the genetic influences underlying the Broad Autism Phenotype. BAP traits which may be the missing heritability puzzle and the genetic influences underlying extreme BAP traits may be a background genetic effect on the neuroanatomical alterations involved in the transition to the handicapping disorder.
Evidence for the two-hit hypothesis has been demonstrated in Downs Syndrome with and without co-occurring autism. Ghaziuddin (1997, 2000) compared a group of Downs Syndrome children and their first degree relatives (parents and siblings) with and without co-occurring autism. In Downs Syndrome with co-occurring autism there was an excess of first degree relatives who met the description of BAP type features compared to first degree relatives in Downs Syndrome without autism who did not. The Downs Syndrome mutation was not present in first degree relatives, parents and siblings, and the genetic influences underlying the BAP component has to be a familial separate component. The genetic influences underlying familial BAP traits appear to be a background genetic effect on the neuroanatomical alterations involved in intellectual disability and severe intellectual disability in Downs syndrome.
Most cases of autism in the single gene disorders are now known to be caused by germ line de novo mutations (egg or sperm). The mutations are not present in either parent and therefore cannot be associated with the genetic influences underlying extreme BAP traits in the families.
There is indirect evidence for the two-hit hypothesis in studying the developmental outcomes, including the prevalence of co-occurring autism, associated with specific pre, peri and neonatal factors in autism etiology. An infrequently used design method was serendipitously introduced by Chess in her 1971 seminal article 'Autism in Children with Congenital Rubella'. In the aftermath of the last rubella epidemic that took place in 1960's in the US, 243 children diagnosed with congenital rubella syndrome were placed under her care at the New York University Medical Center. Of the 243 children, a psychiatric diagnosis of autism was reported in 10 children and a psychiatric diagnosis of atypical autism in a further 8 children which represented 7.4% of the total group.
Studies of outcomes that adhered to Chess's design method of following the developmental outcomes of all children associated with a specific pre, peri or neonatal factor have consistently produced prevalence rates of autism in the range of about 7-8%. The prevalence of autism using this design method are consistent with the co-occurrence of autism in such diverse conditions as as cerebral palsy (8.2%), congenital rubella syndrome (7.4%), premature birth (7.3%), thalidomide embryopathy (4%), newborn encephalopathy (5%) and many other congenital syndromes with an identified medical cause.
The consistent prevalence of autism in these congenital syndromes is consistent with Rutter's two-hit hypothesis and suggests the prevalence of extreme BAP traits in the general population of about 7-8%.
Plomin's group in the UK has been studying the prevalence and heritability of BAP traits and extreme BAP traits in general population twins using autism screening questionnaires such as the CAST and the ASQ in twins recruited from the Twins Early Developmental Study (TEDS) registry. Plomin's group has reported on the prevalence of extreme BAP in the general population: “Around 10% of all children showed only social impairment, only communicative difficulties or only rigid and repetitive interests and behavior, and these problems appeared to be at a level of severity comparable to that found in children with diagnosed ASD in our sample'. Plomin's group also reported that based on cutoffs for the highest 5%-10% CAST and ASQ scores the concordance for extreme BAP traits in general population MZ twins of 57% which is consistent with the concordance rates in narrowly diagnosed MZ twin in the autism twin studies of around 60%. Are the autism twin studies reflecting concordance for extreme BAP traits rather than autism per se?
As the discussions on the search for the 'missing heritability' puzzle continue to become more openly discussed, Rutter's 'two-hit' hypothesis will have to be a large part of the discussion in the coming years.
Anyone interested in obtaining the references with direct links to the abstracts or articles used in this response can request it from me at my Email address at RAJENSEN088@aol.com