HDAC3 Knockout Mice Exhibit Greatly Reduced Loss of Memory Function with Age
Work on the decline of memory formation with aging was presented at a recent conference and is doing the rounds in the press. The core of it was published and presented last year, so the overall topic isn't particularly new, but I didn't notice it at the time. The scientific group in question is interested in the role of histone deacetylases (HDACs) in memory. This is a long-running thread of research. Looking back in the Fight Aging! archives, inhibition of HDACs in the context of improved neural function was mentioned in 2012, and a trail of publications exists prior and since.
The processes of acetylation and deacetylation of histones are important to gene regulation, a core part of the machinery that controls the packaged state of nuclear DNA in the cell nucleus. Genes must be accessible to the machinery of the cell in order to begin transcription, the first step in the complex operations involved in constructing proteins from their genetic blueprints. Whether a specific gene is accessible or inaccessible is determined by the state of various different histones, among other mechanisms. What does this have to do with memory? The formation of memory requires reliable access to certain genes, and the production of their proteins, but it is apparently the case that access becomes less available with age. One of the histones, HDAC3, becomes overactive, keeping DNA more tightly packaged than was the case in younger individuals.
Researchers have now demonstrated that mice lacking HDAC3 do not seem to suffer much in the way of side-effects, and also do not suffer age-related loss of memory - though this effect differs in detail for the various types of memory tested to date. It is worth considering that these mechanisms are a snapshot of some middle layer of the long chain of cause and effect that stretches between the root causes of aging and the ultimate consequences of age-related disease and organ failure. Why does HDAC3 become more active in older individuals? What underlying process is taking place, and what other harms is that process causing? Leaping to interventions has a way of short-cutting the conversation about deeper causes that should be taking place, especially when the interventions are comparatively easy to implement - there are plenty of approaches to HDAC3 inhibition that might be taken at low cost and in the near future, even given the need to bypass the blood-brain barrier. But what is shut out by taking that path as the primary focus?
Research cracks code to restoring memory creation in older or damaged brains
Aging or impaired brains can once again form lasting memories if an enzyme that applies the brakes too hard on a key gene is lifted. "What we've discovered is that if we free up that DNA again, now the aging brain can form long-term memories normally. In order to form a long-term memory, you have to turn specific genes on. In most young brains, that happens easily, but as we get older and our brain gets older, we have trouble with that." That's because the 6 feet of DNA spooled tightly into every cell in our bodies has a harder time releasing itself as needed. Like many body parts, "it's no longer as flexible as it used to be." The stiffness in this case is due to a molecular brake pad called histone deacetylase 3, or HDAC3, that has become "overeager" in the aged brain and is compacting the material too hard, blocking the release of a gene called Period1. Removing HDAC3 restores flexibility and allows internal cell machinery to access Period1 to begin forming new memories.
Researchers had previously theorized that the loss of transcription and encoding functions in older brains was due to deteriorating core circadian clocks. But it was found that the ability to create lasting memories was linked to a different process - the overly aggressive enzyme blocking the release of Period1 - in the same hippocampus region of the brain. That's potentially good news for developing treatments. "New drugs targeting HDAC3 could provide an exciting avenue to allow older people to improve memory formation."
NIH Summit Examines What Makes a Healthy Aging Brain
Histone deacetylase HDAC3 is expressed predominantly in the brain and represses gene expression. Researchers knocked out the HDAC3 gene in the dorsal hippocampi of mice, then trained them at young or old ages on a novel object-location task. Young mice performed equally well, regardless of whether they expressed HDAC3. In older animals the story was different. Wild-type animals became forgetful, whereas HDAC3-deficient mice remembered just as well as did young mice. This suggests HDAC3 hampers memory as mice age. In keeping with this, long-term potentiation weakened with age in wild-type but not HDAC3 knockout mice. Since knocking out HDAC3 restored hippocampal expression of Period1 (Per1), a master regulator of the cellular circadian clock, HDAC3 might function to help regulate circadian genes in the hippocampus.
Histone deacetylases (HDACs) are chromatin modifying enzymes that have been implicated as powerful negative regulators of memory processes. HDAC3 has been shown to play a pivotal role in long-term memory for object location as well as the extinction of cocaine-associated memory, but it is unclear whether this function depends on the deacetylase domain of HDAC3. Here, we tested whether the deacetylase domain of HDAC3 has a role in object location memory formation as well as the formation and extinction of cocaine-associated memories. Using a deacetylase-dead point mutant of HDAC3, we found that selectively blocking HDAC3 deacetylase activity in the dorsal hippocampus enhanced long-term memory for object location, but had no effect on the formation of cocaine-associated memory.
When this same point mutant virus of HDAC3 was infused into the prelimbic cortex, it failed to affect cocaine-associated memory formation. With regards to extinction, impairing the HDAC3 deacetylase domain in the infralimbic cortex had no effect on extinction, but a facilitated extinction effect was observed when the point mutant virus was delivered to the dorsal hippocampus. These results suggest that the deacetylase domain of HDAC3 plays a selective role in specific brain regions underlying long-term memory formation of object location as well as cocaine-associated memory formation and extinction.