Author: Najat Kessler

Histone acetylation: molecular mnemonics on the chromatin

Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.

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Li-Huei Tsai

Li-Huei Tsai: I well remember

Tsai studies how Cdk5 activity affects brain development, learning, and memory.

Cdk5 is a kinase expressed mainly in neurons, where it helps regulate the activity of a whole host of downstream targets, including ion channels and synaptic scaffold proteins. Thus, it’s perhaps to be expected that Cdk5 dysregulation is associated with many neuropathologies.

Li-Huei Tsai cloned Cdk5 as a postdoc and decided she wanted to study it further in her own lab. When asked during job interviews what she would do if Cdk5 wasn’t involved in any interesting phenotypes, she replied that she would no doubt find something else interesting to study. She was soon hired on at Harvard. As it turns out, though, Cdk5 (and its regulation) is plenty interesting, as we learned when we called her at her current lab at the Massachusetts Institute of Technology.

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Re-opening the Memory Book

Following the completion of the Human Genome Project, much of biology’s focus has been shifted from the raw sequence of genes to their regulation over time and in response to environmental stimuli. Like books on a shelf, genes do not exert effects by their mere presence; rather, the pages of the book (i.e., the chromatin) need to be opened so that the words (i.e., the genes) can be read and interpreted correctly. The epigenetic regulation of gene expression refers precisely to this process.

In 1984, Francis Crick (1916-2004) proposed that memory might be coded in alterations to particular stretches of chromosomal DNA. Although the response to this idea was relatively modest at the time, the past decade has shown that chromatin, the carrier of chromosomal DNA, undergoes dynamic modifications and conformational changes during memory formation. One of these modifications is histone acetylation, the addition of an acetyl group to histone proteins. Histone acetylation is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) and generally closely correlates with active gene expression. Rodents display a transient increase in histone acetylation after exposure to various learning paradigms, and synaptic plasticity and memory formation are facilitated after treatment with small molecule inhibitors of HDACs.

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Tsai Lab researchers identify brain cell aberration tied to autism

A gene linked to autism spectrum disorders (ASD) actually alters individual brain cells’ ability to process information, researchers at MIT’s Picower Institute for Learning and Memory report in the June 10 advance online edition of Nature Neuroscience.

The finding focuses on a faulty molecular mechanism that may underlie ASD’s cognitive impairments. The discovery could lead to future treatments targeting a brain enzyme that controls the formation of a neuronal structure called dendrites, according to lead author Li-Huei Tsai, Picower Professor of Neuroscience and director of the Picower Institute.

Dendrites are neurons’ spiky, branchlike projections. Dendrites at the apex of the cell body are known as apical; dendrites that emerge from the bottom are called basal. Basal dendrites, studded with synapses, receive electrical signals sent by other neurons within the brain.

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Reversing Alzheimer’s gene ‘blockade’ can restore memory, other cognitive functions

Neuroscientists show that HDAC2 enzyme could be a good target for new drugs.

MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans. The number of Alzheimer’s victims worldwide is expected to double every 20 years, and President Barack Obama recently set a target date of 2025 to find an effective treatment.

Li-Huei Tsai, leader of the research team, says that HDAC2 inhibitors could help achieve that goal, though it would likely take at least 10 years to develop and test such drugs.

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Unraveling how a mutation can lead to psychiatric illness

MIT neuroscientists show that a gene linked with schizophrenia and bipolar disorder impairs early brain development.

In recent years, scientists have discovered several genetic mutations associated with greater risk of psychiatric diseases such as schizophrenia and bipolar disorder. One such mutation, known as DISC1 — an abbreviation for “Disrupted in Schizophrenia-1” — was first identified in a large Scottish family with high rates of schizophrenia, bipolar disorder and depression.

Studies have since shown that DISC1 mutations can lead to altered brain structure and impaired cognition, but it was unknown exactly how this occurs. A new study from Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, shows that DISC1 mutations impair a specific signaling pathway in neurons that is critical for normal brain development.

In a genetic screen of 750 people — some of whom were healthy and some of whom had psychiatric diseases — the researchers found several common variants of the DISC1 gene. However, even though these mutations disrupted normal brain development, they were not necessarily enough to cause disease on their own.

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