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Mental Retardation: Taking Off the Epigenetic Brakes

23 December 2009. Research on epigenetic effects—heritable changes in gene expression caused by mechanisms, such as methylation, that do not alter DNA sequences—is in its very early days in psychiatry. However, epigenetics is attracting increasing interest among researchers because epigenetic research has suggested intriguing mechanistic links between environmental factors and lasting changes in cognition, behavior, and physiology (see, e.g., Zhang and Meaney, 2010).

Explorations of epigenetics in schizophrenia research are still few and far between (see SRF related news story; SRF news story; SRF news story), but a new study from Paul Greengard's and Alexander Tarakhovsky’s groups at The Rockefeller University of a mental retardation-like phenotype in mice may be a harbinger of like studies in schizophrenia and mood disorders in the coming decade (Renthal and Nestler, 2009).

The technique employed in the new work—a conditional, forebrain-specific, postnatal ablation of GLP/G9a, a histone methyltransferase complex that is crucial for epigenetic gene silencing during normal neural development—is analogous to the alteration of the GLP gene seen in the human 9q Subtelomeric Deletion Syndrome (9qSTDS), and the researchers observed phenotypes in the GLP/G9a-deficient mice that are strikingly similar to those seen in 9qSTDS patients.

A familiar phenotype
9qSTDS is associated with obesity, reduced muscle tone and motor activity, and a gradual decline in goal-directed behaviors and interest in the environment, leading to severe apathy. As reported by co-first authors Anne Schaefer and Srihari Sampath, at about six to eight weeks of age, the GLP/G9a-deprived mice in the new research showed significant declines in exploration and motor activity compared to their normal littermates, and they also showed significant deficits in fear conditioning. By six months of age, GLP/G9a-deprived mice weighed twice as much as controls. GLP/G9a-deprived mice showed virtually none of the marked preference for sucrose over plain water seen in normal mice.

Remarkably, these behavioral phenotypes were not accompanied by any obvious changes in forebrain cell morphology or neuronal architecture: the organization and structure of the hippocampus, striatum, and cortex appeared normal; granule cells, medium spiny neurons, and pyramidal cells were similar to those in control animals.

However, in the hippocampus, striatum, and cortex the researchers found a marked reduction in GLP-positive cells in GLP/G9a-deprived mice, as well as the abnormal presence of non-neuronal cells, whose development in these regions would normally be repressed by methylation effects of GLP/G9a. Immunofluorescence analysis of forebrain neurons confirmed that GLP/G9a methylation was largely abolished in euchromatic DNA, and some 60 genes, including many involved in the differentiation of non-neuronal cells, were found to be upregulated in the forebrain of GLP/G9a-deprived mice, compared to normal littermates.

In separate experiments, the authors specifically ablated GLP/G9a only in forebrain neurons expressing the D1 or D2 dopamine receptor. They did not observe the behavioral phenotypes seen in mice where GLP/G9a had been globally ablated in the forebrain, but did see marked increases in locomotor and exploratory behavior when these mice were treated with either a D1 agonist or with caffeine (which reduces D2 activity by acting as an antagonist at the adenosine-2-α receptor.

The authors attribute the mental retardation-like syndrome they observed to a widespread disruption in forebrain neurons caused by the expression of many non-neuronal genes (or early neuron progenitor genes) unleashed by GLP/G9a deficiency. More narrow disruption, such as that caused in those mice in which GLP/G9a was ablated only in dopaminergic neurons, they argue, may only be revealed by cell type-specific (in this case, pharmacological) stimuli.

“Epigenetic regulators govern expression of large numbers of unrelated genes,” the group writes. “Therefore, it is conceivable that mental retardation is triggered not by changes in specific target gene(s), but by the inability of neurons to respond adequately to environmental signals under conditions of greatly distorted transcriptional homeostasis.”—Pete Farley.

Schaefer A, Sampath SC, Intrator A, Min A, Gertler TS, Surmeier DJ, Tarakhovsky A, Greengard P. Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron. 2009 Dec 10;64(5):678-91. Abstract

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