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Epigenetics of early child development.

Murgatroyd C, Spengler D - Front Psychiatry (2011)

Bottom Line: Here we will review recent studies performed with the common aim of understanding the effects of the early environment in shaping brain development and discuss the newly developing role of epigenetic mechanisms in translating early life conditions into long-lasting changes in gene expression underpinning brain functions.Particularly, we argue that epigenetic mechanisms can mediate the gene-environment dialog in early life and give rise to persistent epigenetic programming of adult physiology and dysfunction eventually resulting in disease.Understanding how early life experiences can give rise to lasting epigenetic marks conferring increased risk for mental disorders, how they are maintained and how they could be reversed, is increasingly becoming a focus of modern psychiatry and should pave new guidelines for timely therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute of Psychiatry Munich, Germany.

ABSTRACT
Comprehensive clinical studies show that adverse conditions in early life can severely impact the developing brain and increase vulnerability to mood disorders later in life. During early postnatal life the brain exhibits high plasticity which allows environmental signals to alter the trajectories of rapidly developing circuits. Adversity in early life is able to shape the experience-dependent maturation of stress-regulating pathways underlying emotional functions and endocrine responses to stress, such as the hypothalamo-pituitary-adrenal (HPA) system, leading to long-lasting altered stress responsivity during adulthood. To date, the study of gene-environment interactions in the human population has been dominated by epidemiology. However, recent research in the neuroscience field is now advancing clinical studies by addressing specifically the mechanisms by which gene-environment interactions can predispose individuals toward psychopathology. To this end, appropriate animal models are being developed in which early environmental factors can be manipulated in a controlled manner. Here we will review recent studies performed with the common aim of understanding the effects of the early environment in shaping brain development and discuss the newly developing role of epigenetic mechanisms in translating early life conditions into long-lasting changes in gene expression underpinning brain functions. Particularly, we argue that epigenetic mechanisms can mediate the gene-environment dialog in early life and give rise to persistent epigenetic programming of adult physiology and dysfunction eventually resulting in disease. Understanding how early life experiences can give rise to lasting epigenetic marks conferring increased risk for mental disorders, how they are maintained and how they could be reversed, is increasingly becoming a focus of modern psychiatry and should pave new guidelines for timely therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus

Experience-dependent activation of neurons in the PVN during early life inhibits MeCP2 binding to and repressing the AVP gene in stressed mice. This further favors DNA hypomethylation underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life.
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Figure 4: Experience-dependent activation of neurons in the PVN during early life inhibits MeCP2 binding to and repressing the AVP gene in stressed mice. This further favors DNA hypomethylation underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life.

Mentions: We then examined the signals controlling MeCP2 occupancy at this early step. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons, which in turn induce a wide variety of cellular responses, connecting neuronal activity to transcriptional regulation (Greer and Greenberg, 2008). Furthermore, neuronal depolarization has previously been shown to trigger Ca2+-dependent phosphorylation of MeCP2, causing dissociation of MeCP2 from the BDNF promoter and consequently gene derepression (e.g., Martinowich et al., 2003). Subsequent studies revealed that CaMKII (Ca2+/calmodulin-dependent protein kinase II) was able to mediate this phosphorylation of rat MeCP2 at serine 421 (Zhou et al., 2006), and the homologous serine residue 438 in the mouse (Murgatroyd et al., 2009). Analysis of 10-day-old early life stressed mice revealed increased CaMKII and phospho-MeCP2 immunoreactivity that promoted MeCP2 dissociation at the AVP enhancer and depression. However, though early life stressed mice tested in adulthood (6 week) still showed reduced MeCP2 binding at the AVP enhancer, the levels of MeCP2 phosphorylation and CaMKII activation in the PVN no longer differed to those of control animals. Instead, evolving differences in DNA methylation at this region underlie reduced MeCP2 occupancy in early life stressed mice. Taken together, the initial stimulus of early life stress initiates a loss of MeCP2 occupancy that subsequently leads to the hard-coding of the early life experience at the level of DNA methylation (Figure 4). Interestingly, in the control mice an age-associated demethylation also occurred though, critically, the region of the enhancer marked by early life stress was spared, supporting, the importance of this region in AVP regulation (Murgatroyd et al., 2010b).


Epigenetics of early child development.

Murgatroyd C, Spengler D - Front Psychiatry (2011)

Experience-dependent activation of neurons in the PVN during early life inhibits MeCP2 binding to and repressing the AVP gene in stressed mice. This further favors DNA hypomethylation underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102328&req=5

Figure 4: Experience-dependent activation of neurons in the PVN during early life inhibits MeCP2 binding to and repressing the AVP gene in stressed mice. This further favors DNA hypomethylation underpinning reduced MeCP2 occupancy at the AVP enhancer and maintaining epigenetic control of AVP expression into later life.
Mentions: We then examined the signals controlling MeCP2 occupancy at this early step. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons, which in turn induce a wide variety of cellular responses, connecting neuronal activity to transcriptional regulation (Greer and Greenberg, 2008). Furthermore, neuronal depolarization has previously been shown to trigger Ca2+-dependent phosphorylation of MeCP2, causing dissociation of MeCP2 from the BDNF promoter and consequently gene derepression (e.g., Martinowich et al., 2003). Subsequent studies revealed that CaMKII (Ca2+/calmodulin-dependent protein kinase II) was able to mediate this phosphorylation of rat MeCP2 at serine 421 (Zhou et al., 2006), and the homologous serine residue 438 in the mouse (Murgatroyd et al., 2009). Analysis of 10-day-old early life stressed mice revealed increased CaMKII and phospho-MeCP2 immunoreactivity that promoted MeCP2 dissociation at the AVP enhancer and depression. However, though early life stressed mice tested in adulthood (6 week) still showed reduced MeCP2 binding at the AVP enhancer, the levels of MeCP2 phosphorylation and CaMKII activation in the PVN no longer differed to those of control animals. Instead, evolving differences in DNA methylation at this region underlie reduced MeCP2 occupancy in early life stressed mice. Taken together, the initial stimulus of early life stress initiates a loss of MeCP2 occupancy that subsequently leads to the hard-coding of the early life experience at the level of DNA methylation (Figure 4). Interestingly, in the control mice an age-associated demethylation also occurred though, critically, the region of the enhancer marked by early life stress was spared, supporting, the importance of this region in AVP regulation (Murgatroyd et al., 2010b).

Bottom Line: Here we will review recent studies performed with the common aim of understanding the effects of the early environment in shaping brain development and discuss the newly developing role of epigenetic mechanisms in translating early life conditions into long-lasting changes in gene expression underpinning brain functions.Particularly, we argue that epigenetic mechanisms can mediate the gene-environment dialog in early life and give rise to persistent epigenetic programming of adult physiology and dysfunction eventually resulting in disease.Understanding how early life experiences can give rise to lasting epigenetic marks conferring increased risk for mental disorders, how they are maintained and how they could be reversed, is increasingly becoming a focus of modern psychiatry and should pave new guidelines for timely therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute of Psychiatry Munich, Germany.

ABSTRACT
Comprehensive clinical studies show that adverse conditions in early life can severely impact the developing brain and increase vulnerability to mood disorders later in life. During early postnatal life the brain exhibits high plasticity which allows environmental signals to alter the trajectories of rapidly developing circuits. Adversity in early life is able to shape the experience-dependent maturation of stress-regulating pathways underlying emotional functions and endocrine responses to stress, such as the hypothalamo-pituitary-adrenal (HPA) system, leading to long-lasting altered stress responsivity during adulthood. To date, the study of gene-environment interactions in the human population has been dominated by epidemiology. However, recent research in the neuroscience field is now advancing clinical studies by addressing specifically the mechanisms by which gene-environment interactions can predispose individuals toward psychopathology. To this end, appropriate animal models are being developed in which early environmental factors can be manipulated in a controlled manner. Here we will review recent studies performed with the common aim of understanding the effects of the early environment in shaping brain development and discuss the newly developing role of epigenetic mechanisms in translating early life conditions into long-lasting changes in gene expression underpinning brain functions. Particularly, we argue that epigenetic mechanisms can mediate the gene-environment dialog in early life and give rise to persistent epigenetic programming of adult physiology and dysfunction eventually resulting in disease. Understanding how early life experiences can give rise to lasting epigenetic marks conferring increased risk for mental disorders, how they are maintained and how they could be reversed, is increasingly becoming a focus of modern psychiatry and should pave new guidelines for timely therapeutic interventions.

No MeSH data available.


Related in: MedlinePlus