Memory
Mouse memories, lost and found again
Lost memories in mice were recovered by enriching their environment, and also by giving them an over-the-counter supplement, sodium butyrate. What can this teach us about Kabuki Syndrome?
How can a mouse brain with severe cell loss still learn again?
Researchers induced memory loss in mice. Then they put the mice in a stimulating environment. The memories came back.
What exactly does the enriched environment do?
It changed the chromatin structure. Specifically, it increased a chemical tag called histone acetylation. This tag helps turn on genes that allow brain cells to form new connections.
Wait, Kabuki syndrome is also linked to chromatin. Is this relevant?
Yes. Kabuki syndrome is caused by changes in KMT2D or KDM6A, genes that directly control histone acetylation. If a healthy brain needs this process to fix itself, it makes sense that a broken version could cause learning problems.
Can this be turned into a treatment for Kabuki?
The study showed that a drug which boosts histone acetylation, an HDAC inhibitor, had the same effect as the enriched environment. It restored learning and memory in the mice. This drug class is a potential therapy for conditions like Kabuki.
What if a brain that has already lost many of its cells could still learn new things—and even recover old memories that seemed gone forever? A remarkable new study suggests that this is possible, and the implications extend directly to conditions where learning and memory are affected, including Kabuki Syndrome.
Neurodegenerative diseases—conditions that destroy brain cells over time—are well known for robbing people of their ability to learn and remember. But this research challenges a long-held assumption: that once significant brain damage has occurred, those abilities are permanently gone.
What the researchers did
Scientists used a special type of mouse that allows them to control when and how severely brain damage occurs. In these mice, a protein called p25—linked to several human neurodegenerative diseases—can be turned on or off by changing the animals' diet. When p25 was activated for six weeks, the mice developed severe learning problems and lost vast numbers of brain cells in the forebrain, the region most involved in complex thinking.
Despite this damage, the mice showed normal anxiety levels and movement, meaning their learning deficits were specific—not just a general sign of being unwell.
Environmental enrichment brought learning back
After the brain damage had already occurred, researchers placed some of the mice into "enriched environments"—larger cages with toys, tunnels, and social companions designed to stimulate their brains. The results were striking.
The enriched mice showed markedly improved learning compared to non-enriched mice with the same amount of brain damage. This improvement came even though the overall extent of brain atrophy was the same in both groups. The enriched mice simply found a way to make better use of the brain tissue they had left.
So how did they do it? The enriched mice showed higher levels of proteins that mark the presence of synapses—the tiny connections between brain cells—and dendrites, the branch-like structures that receive signals. The environment was literally encouraging the growth of new connections. This refinement of the remaining neural network, despite substantial cell loss, may be the key to their recovered learning ability.
The question of lost memories
Learning and memory are not the same thing, as any caregiver for a dementia patient knows. Someone might struggle to learn a new face while also failing to recognize their own child—a long-term memory that should be deeply established.
The mouse model allowed researchers to ask a profound question: when a brain loses cells, are long-term memories actually destroyed, or have they simply become inaccessible? (50)
The researchers trained mice in a fear-conditioning task. They then waited four weeks so the memory would consolidate—moving from a temporary storage site in the hippocampus to more permanent networks in the cortex, similar to the time window reported for human long-term memories. After that, they induced p25 expression for either three weeks (causing no overt pathology) or six weeks (causing severe damage).
Mice with three weeks of p25 expression showed normal memory retrieval. But six-week-induced mice showed almost no evidence of remembering the task. On the surface, the memories appeared lost.
But they weren't lost—they were locked away
Here is where the study makes its most compelling claim. When researchers exposed severely damaged mice to environmental enrichment, those mice showed a marked recovery of long-term memories—far better freezing behavior, indicating they remembered the fearful event. And this recovery happened despite the same extent of neuronal loss and brain atrophy as in non-enriched mice.
The conclusion is profound: the apparent "memory loss" was really a reflection of inaccessible memories. The connections needed to access stored information had been destroyed, but the information itself—somewhere—remained. This is consistent with the phenomenon of "fluctuating memories" seen in dementia patients, who sometimes experience temporary periods of clarity.
The anterior cingulate cortex, a brain region involved in long-term memory, showed reduced synaptic markers in damaged mice but higher levels after enrichment. The enrichment was re-establishing the synaptic network needed for memory access.
How does enrichment work at the molecular level?
Relatively little is known about how environmental enrichment produces its effects, beyond a few genes related to synaptic function. The researchers suspected enrichment might trigger a specific program of gene activity.
They found that within three hours of enrichment, mice showed increased acetylation of histones H3 and H4 in the hippocampus and cortex. Histones are proteins that DNA wraps around, like thread around a spool. Acetylation—adding small chemical groups to histones—loosens that packaging, making genes more accessible to be turned on. This process has been linked to synaptic plasticity and learning.
HDAC inhibitors: a chemical shortcut
If enrichment works through histone acetylation, could a drug that increases acetylation produce similar benefits? The researchers tested two histone deacetylase (HDAC) inhibitors—sodium butyrate and trichostatin A. HDACs are enzymes that remove acetyl groups; inhibiting them increases acetylation.
Kabuki researchers have show interest in studying whether a drinkable HDAC inhibitor, beta-hydroxybuturate (BHB), also available over the counter, could have the same kind of impact on humans.
In wild-type mice, sodium butyrate and trichostatin A significantly improved learning. Sodium butyrate, given daily for four weeks, caused a robust increase in histone acetylation in the hippocampus (68) and improved both associative learning and spatial learning. It also increased markers for synapses and dendrites. Importantly, it did not alter general movement or anxiety, meaning the effects were specific to learning.
These drugs, like enrichment, do not activate genes randomly—non-selective HDAC inhibitors upregulate only 8-20% of all genes analyzed. Both approaches regulate relatively specific transcriptional programs.
HDAC inhibition works even in severely damaged brains
The critical test came next: could HDAC inhibitors restore learning in mice with severe neurodegeneration, just as environmental enrichment had?
Yes. Sodium butyrate-treated mice showed significantly enhanced associative and spatial learning compared to untreated mice with the same amount of damage. Treated mice also showed higher levels of synaptic marker proteins. And again, this happened despite similar extents of brain atrophy and neuronal loss. The learning improvements occurred even while neurodegeneration was ongoing.
In the memory-recovery experiments, the pattern held. Vehicle-injected mice showed impaired access to long-term memories, but sodium butyrate-injected mice showed significantly improved freezing behavior and elevated synaptic markers. The drug recovered long-term spatial memories as well.
What this means
The study makes a clear, evidence-based case: environmental enrichment enables recovery of impaired learning and lost long-term memories, even after severe neurodegeneration and synaptic loss have occurred. This effect is mediated, at least in part, by elevated acetylation of histones H3 and H4, which initiates "rewiring" of the neural network.
These findings extend beyond mice. The researchers note that a brain-injured man who was in a minimally conscious state for 20 years recently experienced spontaneous rewiring and memory recovery. They suggest HDAC inhibitors could potentially re-establish neural networks in human brains and facilitate access to long-term memories in patients with dementia. The re-establishment of a neural network may allow recovery of long-term memories not only in rodents, but also in humans.
The Kabuki connection
For Kabuki parents reading this study, the potential importance is hard to overstate. Kabuki Syndrome is caused by changes in genes—KMT2D or KDM6A—that directly regulate how DNA is packaged around histones and how genes are turned on and off. The very same chromatin-modification machinery at the heart of this study is disrupted by the Kabuki-causing mutations.
The finding that histone acetylation can be increased through environmental enrichment or HDAC inhibitors, leading to improved learning, memory, and synaptic growth even after significant brain damage, suggests a pathway that could be relevant for Kabuki. If a Kabuki brain's learning challenges stem, at least in part, from difficulties in establishing or maintaining synaptic networks—and if those difficulties are tied to histone regulation—then strategies that boost histone acetylation might help.
The study shows that increasing histone acetylation can promote the growth of new dendrites and synapses. It can reinstate learning behavior. And it can recover memories that had become inaccessible. These are precisely the kinds of outcomes that matter to our children.
The researchers acknowledge that different classes of HDACs play distinct roles in synaptic plasticity, and that future research will need to identify which specific HDACs regulate particular forms of learning and memory. Some HDACs also target non-histone proteins, so the effects may be complex. But the principle is established: the brain's ability to learn and remember is not permanently fixed by its genetic blueprint or by the loss of cells. It can be modified, even rescued, after considerable damage has occurred.
For a community of families who think daily about how to help their children's brains build and maintain the connections they need, this study offers genuine hope—grounded not in sentiment, but in carefully controlled science.
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