05:50am Tuesday 22 October 2019

Experience, Interrupted

The developing brain requires ongoing stimulation from the environment to properly fine-tune connections between neurons that are essential for their normal function. According to a new study from Harvard Medical School, serious developmental disorders may result when the processing of environmental stimuli by the brain is interrupted even slightly.

Researchers report that minor alterations to a gene in mice called MeCP2 disrupt the normal development of neural circuits that depend on regular, frequent stimuli and accumulated experience. This suggests that, in humans, similar alterations may contribute to Rett syndrome, a rare autism spectrum disorder characterized by impaired cognition, intellectual deficits and learning difficulties.

These findings, published in Neuron, add to the mounting evidence that experience affects the way genes function in the brain.

Previous work from the laboratory of senior author Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and head of the Department of Neurobiology at HMS, demonstrated that MeCP2 is activated by the biochemical on/off switch known as phosphorylation, a process triggered as the brain responds to external experiences. This suggests, Greenberg said, that experience modifies MeCP2 activity, helping nerve connections in the brain to form and mature.

“By slightly altering the MeCP2 gene in mice,” Greenberg said, “we’ve been able to study in a more nuanced way how experience affects neural development.”

Refining Connections

In this new study, HMS student Sonia Cohen, postdoctoral fellow Harrison Gabel and others in Greenberg’s lab bred genetically engineered mice carrying an alteration in the sequence of the MeCP2 gene. The alteration leaves the MeCP2 protein largely intact but blocks phosphorylation.

Phosphorylation of proteins is used by neurons to sense how often they are stimulated, helping them make long-lasting changes in key structures within the brain that send and receive electrical signals. The refinement of connections between neurons very early in life in response to sensory experience is critical for the proper function of many areas of the brain, including the cortex, a region important for thought and language.

Greenberg has spent 25 years studying experience and brain development. Experience and environmental stimulation, he said, allow nerve connections to mature and create a balance between excitatory and inhibitory neurotransmitters, which stimulate and calm the brain, respectively. The brain’s plasticity and ability to grow and change in response to varying environmental demands enable children to develop language skills, solve problems and get along with others.

While the genetically engineered mice in Greenberg’s study did not display all the deficits of Rett syndrome that mice lacking the entire MeCP2 gene did, the mutant mice, compared with normal mice, showed alterations in the number and pattern of neuronal connections. The mutant mice also showed defects in behavioral responses when presented with new stimuli.

For example, normal mice showed more interest in a novel object than one they had previously encountered, and spent more time interacting with a new mouse than one they had met before. Mutant mice, however, showed little or no preference for new mice or objects. Such defective responses mimic altered interactions with the environment that are characteristic of Rett syndrome.

The next step in Greenberg’s research will be mechanistic, looking in greater detail at how modifications of MeCP2 influence gene expression. Mounting evidence suggests that the MeCP2 protein binds to DNA throughout the nucleus of brain neurons and is involved in regulating the structure of the genome. Understanding how phosphorylation of MeCP2 in response to experience regulates the expression of neuronal genes may explain why MeCP2 is so important for brain development. Such studies, Greenberg said, could provide therapeutic insight into Rett syndrome and other neuropsychiatric disorders.

This research was funded by the National Institutes of Health.

—Scott Edwards

For more information, students may contact Michael Greenberg at michael_greenberg@hms.harvard.edu.

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