Unmasking

Memory Genes
Molecules that expose our genes may also revive
our recollections and our ability to learn
By Amir Levine
CREDIT

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 EPIGENETICS

I
n Rainbows End, by Vernor Vinge, a 2006 science-fiction novel set in the near
future, modern medicine brings a talented Chinese-American poet, Robert Gu,
back from end-stage Alzheimers disease. Before treatment, Gu is bedridden and
can neither talk nor remember his children. After the therapy, his memory returns,
although he develops a different set of talents. Flowers for Algernon, the 1959 short
story by Daniel Keyes, entertains a related fantasy in which a futuristic treatment trans-
forms Charlie, a mentally retarded man, into a genius.
Though fanciful, both these works echo Rescuing Recollections
r esearch hinting that certain chemical treatments In the past few years several scientific teams
can reinvigorate the ability to learn and remember have revealed that making a memory requires en-
even in the face of brain damage or innate mental zymes called histone acetyltransferases (HATs).
deficits. The studies so far done in mice and sea HATs attach chemical units called acetyl groups
slugs indicate that the key to such cognitive im- to histones, thereby opening up DNA and facili-
provements lies in epigenetics, the study of chang- tating gene expression. These enzymes counter-
es in DNA that do not affect the genetic code. In- act the activities of histone deacetylases, or
stead these chemical changes influence gene ex- HDACs, which remove acetyl groups from his-
pression that is, how actively the gene is used to tones and condense DNA.
make protein. Such alterations, it turns out, can One 2004 study, for example, points to the im-
have a profound impact on long-term memory. A portance of HATs in a mouses ability to remember
drug compound, or even an environmental ma- objects and locations. Neuroscientist Mark May-
nipulation, that acts as a kind of volume knob for ford of the Scripps Research Institute in La Jolla,
gene expression could someday help treat memory Calif., and his colleagues engineered mice with an
disorders and facilitate learning. abnormal gene for a HAT called CREB binding
Gene expression is, after all, critical to mem- protein. The inserted gene produced CREB bind-
ory formation. As a person learns and a memory ing protein devoid of all HAT activity, eliminating
takes shape, ebbs and flows in the activity of neu- its capacity to stick acetyl groups onto histones
rons incite the synthesis of new proteins, which near important memory genes. (They engineered
help to cement or create connections between the defect so that it appeared only in adulthood
nerve cells. In this process, genes are first tran- and did not affect development.)
scribed into RNA, which is then translated into These mice displayed distinct memory defi-
protein [see illustration on next page]. cits they had difficulty recognizing familiar ob-
Gene expression is strictly regulated. In chro- jects and recalling the path to a hidden platform
mosomes inside cells, DNA wraps around pro- in a water maze suggesting that normal memo-
teins called histones that serve as packaging ma-
terial. In places where this packaging is looser,
the underlying genes are accessible to the proteins FAST FACTS
that transcribe them, whereas tightly packaged Molecules of the Mind
DNA cannot be transcribed [see The New Ge-
ag e f o t o s t o c k ( D N A ) ; J u p i t e r i m ag e s ( h a n d )

netics of Mental Illness, by Edmund S. Higgins,

on page 40]. Certain chemical changes to DNA
or histones can loosen or tighten this chromo-
1>> Chemical treatments can reinvigorate learning and
memory in rodents, even in the face of brain damage
or inborn mental deficits.
some structure and thereby enable or thwart the
expression of memory genes.
Recently biologists have found that loosening
part of a chromosome using drugs, or environments
2>> One route to cognitive improvement lies in epigenetics,
the study of changes in DNA that do not affect the ge-
netic code but instead influence gene expression that is, how
that provide more intellectual stimulation, can im- actively the gene is used to make protein.
prove learning and memory in cognitively impaired
animals. If such effects can be extended to humans,
future therapies for memory disorders might work
by altering DNA packaging in specific ways.
3>> Future therapies for memory disorders might work by
altering DNA in ways that facilitate gene expression.

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 DNA
tute of Technology and the Howard Hughes
Medical Institute and her colleagues genetically
engineered a group of mice to develop an Alz
heimers-like dementia when the scientists gave
During protein syn-
RNA synthesis
them the antibiotic doxycycline: the antibiotic
thesis, a complex of
(transcription) flipped the genetically programmed dementia
(previously fabricat-
ed) proteins (not switch to the on position at the desired time.
RNA While the mice were still cognitively healthy,
shown) reads a seg-
ment of DNA, using it the scientists taught them to associate an electric
to produce RNA, in shock with a particular chamber so that the mice
a process known Protein synthesis froze in fear whenever they were in the chamber.
as transcription. An- (translation) When the researchers administered doxycycline
other set of mole- to some of the mice, however, those rodents suf-
cules cooperates to Protein fered brain damage and memory loss and forgot
translate the RNA their fear, frequently failing to freeze in the cham-
into a protein, made
Amino acids
ber. In contrast, mice that did not get the antibi-
up of linked amino
otic froze as much as they ever had.
acids. Cellular pro-
teins may participate In an attempt to restore the memory in the
in cell growth, cell brain-damaged mice, the investigators injected
structure or transcrip- some of them daily for four weeks with a chemical
Nerve Transcription that inhibits the acetyl-removing HDACs, a pro-
tion of DNA, among growth factors
Structural
other functions. factors proteins cess that invigorates HATs and unwraps DNA
from its protein packaging. In 2007 Tsais team
ry requires the capacity to attach a sufficient reported that the epigenetic treatment restored the
number of acetyl groups to histones. And to fear memory in the mice that received it and that
prove that the memory impairment resulted from no such memory reappeared in the mice that had
a lack of HAT activity, the researchers showed been injected with an inert saline solution. Chang-
they could abolish the cognitive deficit by com- ing the packaging of DNA and reinvigorating gene
pensating for the molecular one. Gene-altered expression somehow unmasked this simple fear
mice performed normally on the object memory memory probably, the researchers speculate, by
test after receiving a chemical that inhibits spawning new connections between healthy neu-
HDACs, the enzymes that remove acetyl groups, rons rather than by repairing damaged ones.
and therefore boosts the number of acetyl groups The M.I.T. group also came up with a drug-
bound to histones. free way to restore the obliterated fear memory:
But could such a drug recover memories in changing the rodents environment. Enriching the
other situations? Certain clinical phenomena surroundings giving the mice new toys to play
show that memory loss is not always permanent. with and running wheels that enabled them to ex-
When patients emerge from anesthesia after re- ercise similarly increased the number of acetyl
ceiving electric shock treatment for depression, groups on histones, apparently revving up the ex-
their memory returns in stages. At first they re- pression of memory genes just as the HDAC in-
member nothing; then childhood memories hibitors did. Such a finding may help explain why
emerge, and, within minutes, memory lane takes scholars, who presumably live in an intellectually
patients to the present, indicating that recollec- enriched world, are less susceptible to Alzheimers.
tions can indeed reappear after they might seem A mentally stimulating job may be a form of envi-
to have vanished. ronmental enrichment for humans, alleviating the
Animal experiments now indicate that re- effects of neurodegenerative processes in people
trieving lost memories might even be possible af- by loosening chromosome structure.
ter severe neuronal damage and that epigenetic
mechanisms are central to this recovery. Neuro- Correcting Cognition
scientist Li-Huei Tsai of the Massachusetts Insti- If medicine can revive memory after brain de-
edmund S. Higgins

generation, could it also ameliorate inborn men-

(The Author)
AMIR LEVINE is a psychiatrist and neuroscientist at Columbia University.
He is currently investigating the epigenetics of addiction and memory.
tal deficiencies such as those the fictional charac-
ter Charlie displays in Flowers for Algernon? In
a study published in 2004, biologist Angel Barco,
then at the College of Physicians and Surgeons at

50 s c i e n t i f i c a m e r i c a n m i n d J u n e /J ul y 2 0 0 8
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 ( A drug that chemically uncoils DNA restored the
forgotten fear of a shock in brain-damaged mice.
Columbia University, and his colleagues tested
this hypothesis in mice that had a genetic disor-
der resembling Rubinstein-Taybi syndrome,
which in humans leads to mental retardation as
well as skeletal abnormalities such as facial de-
formities and broad thumbs.
Underlying this syndrome is a mutation in the
gene for CREB binding protein. A defect in one
of a persons two copies of the gene renders its
protein nonfunctional; in such cases, cells gener-
ally produce only half the normal amount of pro-
tein. The resulting deficit in CREB binding pro-
tein activity seems to stymie the gene expression
necessary for long-term memories to form, among
its other effects. Similar to what Mayfords group
saw in their HAT-deficient adult mice, Barcos
team confirmed that mice born with a defective
gene for CREB binding protein (and displaying
classic Rubinstein-Taybi-like traits) have poor
long-term memory. In their experiments, the mu-
tant rodents had trouble recollecting having been
shocked in a particular environment or after
hearing a tone. They froze less often than normal
mice did when they were exposed to the setting or
sound that had been paired with the shock.
Mice with the CREB binding protein deficit
displayed no such cognitive problems, however,
if they received an HDAC inhibitor three hours
before their training sessions with the shock, sug-
gesting that the deficit can be reversed by loosen-
ing DNAs protein packaging even if this unrav-
eling occurs belatedly, in adulthood. Such find-
ings hint that the remodeling of this DNA
wrapping might help improve cognition even in
the face of ingrained developmental deficits, pre-
sumably by facilitating the expression of impor-
tant memory genes. In Rubinstein-Taybi syn-
drome, such fixes may directly compensate for
the low rates of acetylation that result from the
lack of functional CREB binding protein.
Other molecules affecting DNAs wrapping
chris newbert Minden Pictures
are also involved in memory and learning. The
sea slug Aplysia, for instance, contains a pair of
compounds called polyADP-ribose (PAR) and
PAR polymerase (PARP), the enzyme that attach-
es PAR to DNAs protein packaging. This enzyme
facilitates transcription by stacking PAR mole-
cules on histones as well as on various proteins
involved in the reading of the DNA template.
To study the role of this enzyme in memory
w w w. S c i A m M in d .c o m scientific american mind
20 08 SCIENTIFIC AMERIC AN, INC.
)
In the sea slug
Aplysia, an
enzyme called
PARP enables
memory forma-
tion by loosening
the structure of
chromosomes.
and learning, the late neurobiologist James H.
Schwartz of Columbia University and his col-
leagues tempted Aplysia with a seaweed these
creatures love and that the researchers had devi-
ously encased in a cotton mesh, making the sea-
weed impossible for the slug to eat. The slugs
learned that the seaweed was inedible and
stopped trying to get it, eliciting the formation
of a long-term memory, which required protein
synthesis. But when the scientists treated some
sea slugs with a compound that inhibits the
PARP enzyme shortly before showing them the
covered seaweed, the mollusks failed to remem-
ber that the food was inaccessible: the next day
they still attempted to eat it. Thus, PARP seems
to be an essential memory enzyme, suggesting
that chemically enhancing its effects could be yet
another avenue for bolstering memory in hu-
mans, who also bear a version of this protein.
Such work, along with the rodent studies, re-
veals the tremendous potential of epigenetic al-
terations to mold memories and, in the future, to
reverse cognitive disorders as diverse as Alz
heimers and mental retardation. A better under-
standing of the systems that modify the packag-
ing of DNA may help us one day make science-
fiction stories such as Rainbows End and
Flowers for Algernon a reality. M
(Further Reading)
u Long-Term Memory Requires PolyADP-Ribosylation. Malka Cohen-
Armon et al. in Science, Vol. 304, pages 18201822; June 18, 2004.
u Chromatin Acetylation, Memory, and LTP Are Impaired in CBP+/ Mice:
A Model for the Cognitive Deficit in Rubinstein-Taybi Syndrome and Its
Amelioration. Juan M. Alarcn et al. in Neuron, Vol. 42, pages 947959;
June 24, 2004.
u Recovery of Learning and Memory Is Associated with Chromatin
Remodelling. Andre Fischer, Farahnaz Sananbenesi, Xinyu Wang,
Matthew Dobbin and Li-Huei Tsai in Nature, Vol. 447, pages 178182;
May 10, 2007.
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