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For Better Memory, Try Keeping Your HAT On…

25 June 2004. …your Histone Acetyl Transferase HAT, that is. In yesterday’s Neuron, two independent laboratories report that the HAT activity of CREB-binding protein (CBP) is crucial for learning and memory. Both groups came to this conclusion by studying models of Rubenstein-Taybi syndrome (RTS); this inherited disorder is caused by mutations in CBP and marked by skeletal malformation and mental retardation. Links between CBP, memory, and Alzheimer’s disease have been growing, most recently with data from Jie Shen’s lab suggesting that γ-secretase, the enzyme which releases amyloid-β peptides, maintains memory thorough a CBP-linked pathway (see Alzheimer Research Forum related news story).

In the first paper, Angel Barco, Eric Kandel and colleagues from Columbia University, New York, and RIKEN, Tsukuba, Japan, used a mouse model of RTS in which one copy of CBP is missing. This models the haploinsufficiency that causes some human forms of RTS. When first author Juan Alarcon characterized these mice, he found that they had normal levels of activity, motivation, anxiety, and short-term memory. However, long-term memory was another matter. Though in a number of tests, including the Morris water maze, the mice performed just as well as those with two copies of CBP, the heterozygous mice performed poorly in fear conditioning and novel object recognition, tasks that rely on storing long-term memories of a single prior event. When re-exposed to mild shock, for example, the RTS mice “froze” less than 15 percent of the time—in contrast, wild-type mice go rigid about 40 percent of the time in the same experiment.

To investigate the reason for this memory deficit, Alarcon and colleagues measured long-term potentiation (LTP), a physiological response in neurons that is both easily measured and essential for memory. Alcaron found that neurons in CBP-heterozygous animals have normal early LTP, but late LTP—which requires transcription—was attenuated, thus linking the memory defect to protein synthesis.

This connection makes sense because CBP is a co-factor for the transcriptional activation of many proteins. But is it the HAT activity of CBP that it particularly essential for LTP and memory, or something else? To address this, Alarcon examined the acetylation state of histones in the CBP+/- animals, finding that histone H2B in particular was reduced by about 50 percent. This suggests that the acetylation activity might be the missing component, a finding that was supported by giving the mice drugs that block deacetylation. When the histone deacetylase inhibitor suberoylanilide hyroxamic acid (SAHA) was introduced into the brain ventricles a few hours before a contextual fear conditioning experiment, the mice scored as well as normal animals.

In the second paper, Mark Mayford and colleagues at The Scripps Research Institute, La Jolla, and the University of San Diego, arrived at almost the same conclusions, though based on a slightly different model. By generating transgenic mice that express CBP with an inactive HAT domain, first author Edward Korzus directly tackled the question of which CBP activity is linked to RTS. In characterizing these mice, he also found that the animals had normal short-term memory but found them lacking when it came to the long-term memory needed for novel object recognition. Animals missing the CBP HAT domain performed about 30 percent less well than did wild-type mice. Korzus, too, found no difference between the HAT-negative mice and wild-type in the Morris water maze.

Significantly, the model Korzus chose eliminates developmental defects as an explanation for the memory impairment. He placed expression of the transgene under the control of a doxycyclin-sensitive promoter, and only after doxycycline was withheld from the diet of adult mice did they run into trouble with their long-term memories.

As in the Alcaron et al. study, Korzus and colleagues used a histone deacetylase inhibitor, in this case trichostatin A, to try to reverse the memory impairment. Injecting the inhibitor two hours before testing leveled the playing field for the transgenic mice, as SAHA had done in the first paper. However, it is interesting to note that Korzus found that histone H3 was preferentially acetylated in the presence of trichostatin, not histone H2B. This suggests that acetylation of different histones can rescue long-term memory deficits.

“Together, Alarcon et al. and Korzus et al. illuminate a central role for the histone acetyltransferase activity of CBP in long-term memory, providing strong support for the idea that chromatin remodeling serves to maintain memories,” write Kelsey Martin and Yi Sun from the University of California, Los Angeles, in an accompanying preview. The studies also shed light on the potential new “epigenetic therapeutic” approaches to treating mental retardation and other neurologic diseases, Martin and Sun write. Alzforum readers may already be familiar with the potential of histone deacetylase inhibitors, which have been shown to slow neurodegeneration in fruit fly models of polyglutamine diseases (see Alzheimer Research Forum related news story).—Tom Fagan

Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: A model for the cognitive deficity in Rubinstein-Taybi syndrome and its amelioration. Neuron 2004. June 24;42:947-959. Abstract

Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 2004. June 24;42:961-972. Abstract

Martin KC, Sun YE. To learn better, keep the HAT on. Neuron 2004. June 24;42:879-881. Abstract

Comments on Related News

Related News: On Again, Off Again—DNA Methylation, Genes, and Plasticity

Comment by:  David Yates
Submitted 18 April 2007
Posted 26 April 2007

Are these studies of relevance to the report from Israel that older men feed their mutations into the gene pool and this in part accounts for keeping the “schizophrenia gene” going despite poor fertility (Malaspina et al., 2002)? And might a comparison of the DNA of healthy siblings born before the mutations of an “older man” mutation with that of a sibling who got such a later mutation and developed schizophrenia reveal something of interest?

View all comments by David Yates