376

Edwin J. Weeber, Jonathan M. Levenson, J. David Sweatt
Division of Neuroscience, Baylor College of Medicine
1 Baylor Plaza, Houston, TX 77030

Molecular

Genetics

of Human

Cognition

A

n intimate relationship exists between our capacity for

learning and memory and the domains of human

cognition. This relationship becomes all too clear when a

genetic disruption causing the diminished capacity for

memory formation results in an individual with a pronounced

cognitive deficit. Only recently, through the identification of

human genetic mutations that result in mental retardation

and learning disorders, have we begun to gain some insight

into the genetic and molecular basis of human cognition. The

following review describes some of the genetic causes and

biochemical consequences of several recently identified

genetic disorders that result in a disruption of memory

formation and subsequent decline in human cognitive

function.

I

NTRODUCTION

Cognition can be defined as the active
intellectual processes through which
information is obtained, transformed,
stored, retrieved, and used by the
brain. The ability to form long-lasting
memories and to retrieve these
memories when necessary is the axis
upon which human cognitive ability
revolves. Memory formation not only
defines who we are as a species in our
capacity for learning, but our personal
memories and experiences help to
define who we are as individuals. It
should be recognized that the capacity for this basic, intrinsic
ability to form new memories is ultimately genetic in origin. This
becomes extremely evident when a genetic aberration causes a
disruption in the capacity for memory formation and manifests in
an individual as a pronounced cognitive deficit.

We have reached a point where clinical and basic science

research have converged and provide us insight into the molecular
basis of human cognition. Only recently have neuroscience
researchers begun to solve any of the mysteries surrounding
proteins and signaling pathways that underlie the formation of
lasting memory in the mammalian brain. In parallel, clinical
research has identified many genes responsible for human learning
disorders. Thus, we are at a point where new hypotheses can be
formulated concerning the molecular mechanisms that underlie
human mental retardation syndromes. Additionally, the
identification of specific genes and their products in human
disorders that are associated with mental retardation has greatly
facilitated our understanding the basic mechanisms involved in
the formation of human memories.

The following review examines the genetic causes and

biochemical consequences of several recently identified disorders
that result in a disruption of human cognitive ability. Although our
understanding of many of these disorders is incomplete and still
under intense investigation, we discuss the implications of the
emerging molecular basis of these disorders on our current
understanding of learning and memory mechanisms. One focus of
our review will be how new, genetically engineered mouse models
of human mental retardation syndromes have given us insight into
the molecular biology of human learning disorders.

M

EMORY

F

ORMATION

: A M

OLECULAR

P

RIMER

Much progress has been made in the last decade toward
understanding the molecular blueprint for long-term memory
formation in the mammalian brain. Long-term memory formation
begins at the plasma membrane of neurons, at synapses located on
dendritic spines. High frequency presynaptic activity at these sites

leads to the release of glutamate, which activates a host of
glutamate receptors on the postsynaptic spine (Figure 1).
Glutamate receptors are generally divided into two broad
categories: ionotropic and metabotropic. Ionotropic receptors are
ligand-gated channels that can depolarize the membrane [i.e.,

-

amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and
kainate subtypes] or allow calcium influx [i.e., N-methyl-

D

-

aspartate (NMDA) receptors]. Metabotropic receptors are coupled
to intracellular second messenger cascades. High-frequency
stimulation results in a large postsynaptic depolarization, which
allows for activation of the NMDA-subtype of ionotropic glutamate
receptors leading to Ca2+ influx into the spine. Moreover, the
attendant high levels of glutamate allow for activation of
metabotropic glutamate receptors, which are coupled to the
phospholipase C (PLC) pathway. The increase in intracellular Ca2+
and the activation of metabotropic glutamate receptors in the
spine leads to activation of a number of postsynaptic protein-
kinase signaling pathways, including the Ca2+-calmodulin kinase
II (CaMKII), cAMP-dependent protein kinase (PKA), protein
kinase C (PKC) pathways, and the Ras pathway. One downstream
target that is activated by all of these pathways is the mitogen-
activated protein-kinase (MAPK) termed extracellular-regulated
kinase (ERK). Once stimulated, ERK phosphorylates and activates
ribosomal S6-kinase 2 (RSK2), which in turn phosphorylates the
transcription factor cAMP response-element (CRE) binding protein
(CREB). CREB recruits a number of transcriptional coactivators,
including CREB binding protein (CBP), and initiates a wave of
transcription that is vital for the consolidation of long-term
memory. Newly synthesized transcripts must be transported out of

Genes and Proteins Involved in Cognition

377

October 2002

Volume 2, Issue 6

Ca

2+

Signal Transduction Cascades

CREB-mediated

transcription

Protein synthesis

Long lasting changes in synaptic efficacy

- Altered electrical properties of membrane

- Increased glutamate receptor expression

- Changes in synaptic morphology

- Increased number of synapses

Glutamate

Figure 1. Processes involved in memory formation. Formation of
memory is a complex process that requires several aspects of cell function.
Memory formation begins at the plasma membrane. Upon activation,
NMDA-type glutamate receptors allow Ca2+ to flow into the cell. The Ca2+
flux activates several second-messenger signaling cascades. Ultimately, these
signaling processes activate the transcription factor CREB, which leads to
the modulation of several genes required for consolidation of long-term
memory. Translation of newly synthesized mRNAs leads to production of
proteins required to affect long-term changes in neuronal physiology.

the nucleus and translated into functional proteins, which effect
lasting changes in synaptic strength by altering the electrical
properties of the membrane, increasing the responsiveness to
neurotransmitter, and even changing the number and size of
synapses.

The formation of memory, thus, depends upon the

coordination of numerous cellular processes. A consequence of the
complexity of memory formation however, is that disruption of
one, or a few of the molecular steps involved can be deleterious.
For example, deficits in human memory formation (i.e., mental
retardation) are caused by specific defects in the molecular
pathways responsible for memory formation. In the sections that
follow, we will explore the molecular basis of some molecular
defects along this pathway that result in cognitive deficits in
humans.

C

ELL

S

IGNALING

: D

EFECTS IN

I

NFORMATION

-F

LOW

FROM THE

M

EMBRANE TO THE

N

UCLEUS

Recent work has shown that a number of signaling cascades must
be activated to successfully form long-term memories. In
retrospect, it is not surprising then, that a number of deficits in
human cognition arise from derangements in the functioning of
these signaling pathways vital to the formation of memory.

A

NGELMAN

S

YNDROME

Angelman Syndrome (AS) is a severe form of mental retardation
that occurs in one of every 15,000–20,000 births. AS is usually
accompanied by epilepsy, a puppet-like gait, dysmorphic facial
features, a happy disposition with bouts of inappropriate laughter,
hyperactivity, sleep disorders, and lack of speech (1, 2).

In 1997, the gene responsible for AS was identified as the

ubiquitin-protein ligase, Ube3a (3, 4). An unusual characteristic of
this defect is that the Ube3a locus undergoes imprinting, whereby
only the maternal allele is active in specific tissues. The paternal
silencing of the Ube3a gene occurs in a brain region-specific
manner; the maternal allele is active almost exclusively in the
hippocampus and cerebellum (5). The most common genetic
defect leading to AS is an ~4 Mb maternal deletion in
chromosomal region 15q11–13 causing an absence of Ube3a
expression in the maternally imprinted brain regions. Ube3a codes
for an E6-AP ubiquitin ligase, an enzyme involved in the
ubiquitin-proteasome pathway. Ubiquitination targets proteins for
degradation through the proteasome pathway. However, E6-AP
ubiquitin-ligase chooses its substrates very selectively and the four
identified E6-AP substrates have shed little light on the possible
molecular mechanisms underlying the human AS mental
retardation state. The development of mouse models for AS has
increased our understanding of the genetic alterations and
physiological consequences underlying this disorder.

There are two mouse models for AS which replicate the

abnormalities and brain-specific imprinting of Ube3a observed in
humans (3, 6, 7). The mouse model developed by Jiang et al. has
provided a variety of information regarding the neural basis of the
cognitive defects caused by AS (7). Initial studies of mice that do
not express maternal Ube3a showed severe impairments in
hippocampal memory formation (7). Most notably, there is a
deficit in a learning paradigm that involves hippocampus-
dependent contextual fear conditioning. In addition, maintenance
of long-term synaptic plasticity in hippocampal area CA1 in vitro
is disrupted in Ube3a–/– mice (7). Thus, current research using
this mouse model focuses on the molecules required for
hippocampal synaptic plasticity. The results from murine gene-
knockout studies provide a link between hippocampal synaptic
plasticity in vitro and formation of hippocampus-dependent
memory in vivo, and suggest that the expression of synaptic
plasticity, as measured by LTP formation, underlies human
hippocampus-dependent memory formation.

N

EUROFIBROMATOSIS

One of the most common single-gene disorders causing
cognitive disorders in humans is Neurofibromatosis type 1
(NF1), which affects approximately one in 4,000 individuals.
The predominant phenotypic characteristic of NF1 is the
development of benign neurofibromas of the peripheral
nervous system. Other clinical manifestations include
malignant tumors (gliomas or malignant peripheral nerve
sheath tumors), skin discoloration, and skeletal dysplasia. NF1
leads to varying levels of mild cognitive impairment in
40–65% of patients (8). The heterogeneity of NF1 gene
mutations is thought to contribute to its lack of complete
penetrance for various phenotypes, including cognitive
disruption (9).

The product of the NF1 gene, neurofibromin, is highly

expressed in brain during embryogenesis, and in adults it is
primarily expressed in pyramidal and Purkinje neurons, Schwann
cells, and oligodendrocytes. NF1 mRNA undergoes alternative
splicing resulting in four different protein isoforms (type I-IV);
however, the predominant neuronal forms are produced through
alternative splicing of exon 23a, resulting in type I (NF1-I,
exclusion of exon 23a) or type II (NF1-II, inclusion of exon 23a)
protein (10).

Exon 23a contributes to the regulation of GAP [guanosine

triphosphatase (GTPase) Activating Protein] activity intrinsic to
NF1 (Figure 2). This domain (including the GAP) is important for
interactions of NF1 with Ras (10), a low molecular weight GTPase
that acts as a critical relay in signal transduction by cycling
between an active conformational state (Ras·GTP) and an inactive
state (Ras·GDP) (Figure 2A). The GAP activity of NF1 promotes
the hydrolysis of GTP and the formation of Ras·GDP, thus
inhibiting Ras activity. Guanine nucleotide exchange factors
(GEFs) counterbalance the effects of GAP proteins by catalyzing

Review

378

the exchange of GDP for GTP, leading to increased amounts of
Ras·GTP. Therefore, loss of NF1-dependent inhibition of Ras could
lead to the learning deficits seen in NF1 (11).

In a series of elegant studies, Costa et al. investigated the role

of Ras in the cognitive disruption of NF1 (12). NF1 heterozygous
knockout animals, which show a deficit in spatial learning, were
crossed with animals deficient in Ras activity. Remarkably, the
genetic diminishment of Ras activity was sufficient to rescue the
spatial learning deficit observed in the NF1 heterozygous mice.
Additionally, learning deficits were rescued in NF1-heterozygous
animals treated with a farnesyltransferase inhibitor, suggwsting
that hyperactivation of the Ras pathway is the likely cause of
learning deficiencies in NF1-deficient mice and patients with NF1.

The question remains: what are the downstream targets of

Ras hyperactivation that lead to cognitive disruption? Ras regulates
the Raf–ERK cascade in a variety of cells, including hippocampal
neurons (Figure 2B). Therefore, it is likely that the ultimate
consequence of hyperactivation of the Ras signal transduction
cascade lies in the dysregulation of one or more ERK-regulated
transcription factors, including CREB, Elk-1 and c-Myc.

C

OFFIN

-L

OWRY

S

YNDROME

Coffin-Lowry Syndrome (CLS) is an X chromosome-linked
disorder. Affected males with CLS are characterized by an
abnormal gait, facial abnormalities (protruding forehead, wide
noses, and irregular teeth), skeletal abnormalities (osteopenia,
short stature, and muscular hypodevelopment) and severe mental
retardation (13, 14). As with other X-linked disorders,
heterozygous females exhibit similar but much less severe
characteristics. Before the development of reliable genetic testing
for the disease, CLS was often misdiagnosed because of the
variability in its manifestation, which mimics many other X-linked
mental retardation conditions.

CLS is caused by a disruption of the gene encoding the 90-

kDa ribosomal S6 serine-threonine kinase-2 (Rsk2), located at
Xp22.2. Early studies of the Rsk2 gene and analyses of Rsk2
mutations from CLS patients have revealed that a wide variety of
mutations of the Rsk2 gene—including splice alterations, missense,
frame-shift and nonsense mutations—are responsible for CLS (15).
Initially identified as a ribosomal S6-kinase, Rsk2 also
phosphorylates and activates a number of nuclear proteins
including CREB (15, 16). In the CNS, the ERK signaling pathway
activates of Rsk2, which is responsible for PKA-dependent CREB
activation in the hippocampus (Figure 2B).

Dufresne et al. have produced a viable, Coffin-Lowry mouse

model through the disruption of Rsk2 (17). Rsk2 mutant mice
exhibit deficits in motor learning and coordination, and have
severe deficits in spatial learning. However, much of what can be
inferred about the role of Rsk2 in cognitive function has come
from studying the activity of ERK1, ERK2, and CREB in synaptic
plasticity and memory formation. The requirement for the ERK
and CREB in synaptic plasticity and formation and consolidation
of long-term memories is well established. Thus, molecular
components of memory formation up- and downstream of Rsk2
are involved in mammalian cognition. Yet, many questions still
exist about the role(s) of Rsk2 in neuronal function and the mental
aberrations seen in CLS. For example, evidence implicates Rsk2-
mediated phosphorylation of SOS, a GEF for Ras, as a possible
mechanism for negative-feedback regulation of the
Ras–MEK–MAPK pathway (18). Further investigation of the
mechanisms underlying deficits in synaptic plasticity and memory
formation in CLS-model mice will be necessary.

Genes and Proteins Involved in Cognition

379

October 2002

Volume 2, Issue 6

PKC

PKA

Raf-1

Rap1

MEK

ERK

RSK2

Ras

Ras

Inactive

Active

GDP

GTP

NF1

GAP domain

GEF

GTP

GDP

DMPK

A

B

Ras

B-Raf

Elk-1

CREB

Figure 2. Signaling pathways implicated in human memory formation.
A. Ras is a small GTPase whose activity is regulated by the presence of GTP
or GDP. When bound to GDP, Ras is inactive. Guanine nucleotide exchange
factors (GEF) catalyze the exchange of a molecule of GDP for a molecule of
GTP. Once bound to GTP, Ras is activated. GTPase activating proteins
(GAP) promote the hydrolysis of GTP to GDP, inactivating Ras. NF1
contains a GAP, and is involved in inactivation of Ras. B. Signaling through
PKA and PKC leads to activation of ERK/MAPK. In parallel, Raf-1 also
activates the DM1-associated protein kinase (DMPK) involved in myotonic
dystrophy. RSK2 is activated by ERK, and regulates gene transcription. CLS
is due to disruption of RSK2.

C

OGNITIVE

D

ISRUPTION AT THE

N

UCLEUS

Changes in cellular physiology due to the direct action of various
second messengers and signaling pathways are short-lived at best.
Long-term changes in cell function are usually effected through
changes in expression of one or more genes. Thus, ultimately gene
expression is necessary for the integration of external signals with
long-term internal cellular function. It is not surprising that many
diseases of cognition are due to derangement of nuclear function.

D

OWN

S

YNDROME

: A

BERRANT

G

ENE

D

OSAGE

First described by John Langdon Down in 1866, Down Syndrome
(DS) is the most common form of mental retardation. DS occurs in
one out of 800 live births, and accounts for nearly 30% of
moderate to severe mental retardation. There are a number of
stereotypical physical attributes associated with DS including short
neck, short broad hands, flat nasal bridge, and narrow palate. IQs
of DS patients range from 40–70, depending on the severity of the
illness. Individuals with DS display a pronounced delay in the
development of language, and exhibit deficits in various forms of
short-term and spatial memory. There is an increased risk for early
development of Alzheimer dementia, which usually occurs around
age thirty-five.

The molecular basis for DS is the presence of an extra copy of

chromosome 21, referred to as trisomy 21 (Ts21). Chromosome
21 is 45 Mb long and contains 303 genes. A region of ~5 Mb of
chromosome 21 has been implicated in the development of mental
retardation in DS patients (19), and within this critical region lie
several genes that may affect memory formation (20).
Overexpression of genes from this locus is thought to interfere
with their normal regulation and to lead to the cognitive deficit in
DS (21). Two mouse models with trisomy have been generated
(Ts16, Ts65Dn), both of which mimic most of the DS human
phenotype including severe memory impairments (20). In the
following sections we will briefly review some of the more
prominent genes in this region.

Perhaps the most notorious gene the critical region of

chromosome 21 encodes is the amyloid precursor protein (APP).
The APP-derived peptide known as amyloid beta peptide (A

) is

one of the primary components of the plaques found in the brains
of Alzheimer’s disease patients (22). Mice that overexpress A

 have

deficits in LTP induction and memory formation (23). Recently,
Dineley et al. (24) showed that A

 can activate the ERK signaling

cascade through

7-nicotinic acetylcholine receptors. Moreover,

A

-dependent dysregulation of ERK signals leads to aberrant

increases in phosphorylation of CREB (24). As mentioned above,
the ERK–CREB signaling pathway is essential in the formation of
long-term memories in a number of different organisms.

Another gene present on chromosome 21 implicated in

memory formation is the Cu2+/Zn2+ superoxide dismutase
(SOD1) gene. Superoxides can potentiate synaptic transmission

and are required for induction of hippocampal LTP in vitro (25,
26). In mouse models, overexpression of SOD, as would occur in
DS, leads to decreases in ambient levels of superoxide and impairs
induction of hippocampal LTP in vitro and hippocampus-
dependent long-term memory formation in vivo (27).

DYRK1A, the human homolog of the Drosophila Minibrain

kinase, is also well studied. DYRK1A is located in the DS-critical
region of chromosome 21 and is expressed in several structures of
the adult CNS including the cortex, hippocampus and cerebellum
(28). Dyrk1A expression is significantly elevated in the CNS
during development in DS humans and in a mouse model for DS,
Ts65Dn (29). Transgenic mice that overexpress Dyrk1A
(TgDyrk1A) display several behavioral abnormalities that are
similar to those seen in DS. Specifically, TgDyrk1A mice are
delayed in their acquisition of mature locomotor skills and have
deficits in spatial learning (30).

Human Ts21 neurons appear to have significantly different

passive electrical properties from normal diploid neurons (20).
Ts21 neurons are more excitable at rest, and show dramatically
different rates of action potential depolarization and repolarization
(20). Neurons isolated from Ts16 mice, the other mouse model for
DS, also have abnormal, passive electrical properties; however, the
differences observed do not exactly replicate those found in the
human disease (20). Not surprisingly, there are several genes on
human chromosome 21 involved in the regulation of neuronal
excitability, including the inward-rectifying K+ channels
Kcnj6/Kir3.2, Kcnj15/Kir4.2, and Kcne1 (20).

R

ETT

S

YNDROME

Andreas Rett, an Austrian pediatrician, first described Rett
syndrome (RS) in 1966 (31). In the United States, RS did not gain
major attention until 1983, when it was further characterized by
Hagberg et al. (32). RS is an inherited, X-linked disease that afflicts
about one in 15,000 females by ages 2–18 years of age, and is
estimated to be the second leading cause of mental retardation in
women, behind DS (33). Development during the first six months
of life is normal in RS patients, with symptoms appearing between
three months to three years. The trademark of RS is display of
continuous, stereotypical hand movements, such as wringing,
washing, clapping or patting, which appear after the loss of
purposeful hand movement. Other signs of RS include decreased
growth (including microcephaly), abnormal respiration, gait ataxia,
autism, seizures and other neurologic dysfunctions. Several
mapping studies narrowed the location of the putative RS locus to
Xq28 (34), and in a percentage of patients, a mutation of the
methyl CpG binding protein 2 (MeCP2), whose gene is located in
Xq28, is correlated with Rett syndrome (35).

MeCP2 functionally connects DNA methylation to gene

silencing (Figure 3). DNA methyltransferases catalyze the
methylation of cytosine at position 5 using S-adenosylmethionine
as a methyl donor. Methylation usually occurs at CpG (cytosine,

Review

380

phosphorylated guanine) dinucleotides. The distribution of CpG
in the genome is not random; most CpG is found in repeating
sequences and in CpG-enriched areas (islands). Interestingly, CpG
islands are most commonly found in the promoter region of genes.
Once methylated, 5mCpG is bound by MeCP2, which then
recruits a complex of proteins including histone deacetylases and
transcriptional corepressors such as Sin3A (36). Ultimately, the
histones associated with the 5mCpG become hypoacetylated,
promoting tight association between the DNA and the histones
and resulting the formation of a stable, transcriptionally-repressive
chromatin complex.

The role that MeCP2 might play in the memory deficits

observed in RS is still unclear. DNA methylation is involved in
genome imprinting and dosage-compensation. Therefore, MeCP2
would be predicted to play a prominent role during development.
Indeed, early attempts to create mice lacking MeCP2 resulted in
embryonic lethality (37). However, RS is a progressive disease that
does not result in symptoms until early childhood. More recent

attempts to create MeCP2-deficient mice have succeeded (38, 39).
These mice display some of the characteristics of RS including
reduced brain and body size, tremors, hypoactivity, and irregular
gait (38, 39). However, there are no studies detailing the cognitive
performance of these mice.

Another strain of mouse has been developed that more

closely approximates the mutations commonly found in RS
patients (40). In this mouse model, the last one-third of MeCP2’s
protein-coding region was removed (MeCP2308/y) (40).
MeCP2308/y mice share phenotypic similarities with RS including
seizures, impaired motor coordination, hypoactivity, increased
anxiety, and display some repetitive forelimb movement (40).
However, MeCP2308/y mice have no memory deficits, suggesting
that either MeCP2 does not account for the entire RS phenotype,
or that this particular MeCP2 mutation does not exactly replicate
all the cognitive aspects of RS.

R

UBINSTEIN

-T

AYBI

S

YNDROME

Described by Rubinstein and Taybi in 1963 (41), Rubinstein-Taybi
Syndrome (RTS) occurs approximately once in every 125,000 live
births, and accounts for one in 300 patients with mental
retardation. There are several physical traits associated with RTS
including altered facial features, broad digits, and blunted growth
(42). RTS is an inherited, autosomal dominant disease. Genetic
studies have determined that the locus responsible for RTS maps
to chromosome 16p13.3, which contains the gene for the
transcriptional coactivator CREB-binding protein (CBP) (43).
Subsequent studies have shown that RTS patients have a variety of
mutations in CBP, including point mutations and 5'- or 3'-
deletions (44). It should be noted that patients are typically
heterozygous for a mutation in CBP, suggesting that RTS is due to
either haploinsufficiency or a dominant-negative effect (43).
Homozygous mutations of CBP are likely embryonic lethal in
humans. Homozygous CBP-deficient mutant mice die in the early
embryonic stage (E10.5–E12.5), apparently as a result of massive
hemorrhage caused by defective blood vessel formation in the
CNS, and exhibit developmental abnormalities as well as delays in
both primitive and definitive hematopoiesis.

CBP is important in linking CREB activation to gene

transcription. The transcription factor CREB lies dormant in the
nucleus until activated by phosphorylation. Once activated,
phospho-CREB (P-CREB) recruits CBP and binds to CREs within
the DNA (Figure 4). CBP is thought to acetylate histones
associated with the CRE, disrupting the chromatin within the
promoter and facilitating the binding of the RNA polymerase II
holoenzyme (45). Therefore, an increase in CREB-mediated
transcription is associated with an increase in histone acetylation,
especially histones located near CREs. Indeed, several studies
indicate that histone acetylation accompanies increases in CREB-
dependent transcription (45).

CREB plays an important role in consolidation of long-term

Genes and Proteins Involved in Cognition

381

October 2002

Volume 2, Issue 6

Figure 3. Repression of transcription via methylation. DNA
methyltransferases (MeT) catalyze the methylation of cytosine, producing
5

'

-methylcytosine (5mC). Most cytosine methylations occur in cytosine

phosphorylated guanine (CpG) dinucleotide repeats (islands). The
transcriptional repressor, methyl-CpG binding protein 2 (MeCP2), binds to
5mCpG and recruits histone deacetylases (HDAC) and corepressors, such
as Sin3a. The activity of this protein complex causes a change in chromatin
structure such that transcription is blocked. Rett syndrome is believed to
be caused by disruption of MeCP2.

CpG island

MeT

Promoter

MeCP2

Sin3a

HDACs

CH3

CH3

CH3 CH3 CH3 CH3

CH3 CH3 CH3

CH3 CH3 CH3

MeCP2

Sin3a

HDACs

Transcription blocked

memory. If CBP is vital for CREB-mediated transcriptional
regulation, it follows that CBP would also be important for long-
term memory formation. Therefore, mutations in CBP or
disruption of CBP expression would be predicted to lead to
impairments in memory formation, such as those seen in RTS.
Two different strains of mice with mutated CBP alleles have been
studied (46, 47). The first strain, which contains a null mutation
leading to haploinsufficiency, had no memory impairments (46).
However, the second strain, which was heterozygous for a
dominant-negative mutant form of CBP that possessed only the
CREB binding domain (CBPDN), mimicked nearly all aspects of
RTS (47). Specifically, CBPDN mice had altered facial features and
stunted growth (47). Moreover, CBPDN mice had dramatic deficits
in long-term memory formation, with normal short-term memory
(47), suggesting that RTS is caused by a dominant-negative
mutation in one allele of CBP. Furthermore, these results
demonstrate that CBP plays a critical role in the consolidation of
long-term memory. The histone-acetyl transferase (HAT) activity
possessed by CBP, was absent from the CBPDN mice, might
specifically underlie the deficits in consolidation of long-term
memory. If the HAT activity is indeed the critical factor underlying
RTS, then this suggests that histone deacetylase inhibitors might
be able to treat this disease.

M

YOTONIC

D

YSTROPHY

Muscular dystrophy describes a class of diseases whose ultimate
pathology is striated muscle wasting and eventual death. The

most common form of muscular dystrophy, myotonic dystrophy
(DM1) occurs once in every 8,000 live births (48). Symptoms
usually begin to appear in adulthood, and include mild mental
retardation, myotonia, abnormal cardiac conduction,
hypersomnia, cataracts, insulin-dependent diabetes, and
testicular atrophy, and premature balding in men. Congenital
cases of DM1 are more pronounced than cases of DM2, and
characteristics include severe mental retardation, hypotonia,
facial dysplegia, inability to feed and respiratory problems. We
will focus on the molecular basis of the cognitive impairments
associated with DM1.

DM1 is an inherited, autosomal dominant disease that has

been mapped to chromosome 19q13.2–13.3 (49). Subsequent
studies identified DM1-associated protein kinase (DMPK) as the
gene mutated in DM1. The exact mutation responsible for DM1
was determined to be an unstable CTG repeat located in the 3'-
untranslated region (UTR) of DMPK (Figure 4) (49). DM1 is one
member of a class of cognitive diseases whose basis lies in
expansion of trinucleotide repeats (see FMR1 and FMR2 below).
In the general populace, DMPK contains from 5–27 CTG
repeats, whereas in DM1 thousands of repeats can be present.

The molecular basis of DM1 involves the dysregulation of a

whole host of genes. Expansion of CTG repeats in the 3'-UTR of
DMPK can have several consequences on cellular function. CTG
repeats favor nucleosome assembly and a condensed chromatin
structure (50). Indeed, experimental evidence indicates that in
DM1, the CTG repeats in DMPK favor condensed chromatin
(51). Condensed DNA is not accessible for binding by non-

Review

382

Nucleus

ERK

RSK2

CREB

CBP

MeCP2

Trinucleotide Repeat

Trisomy 21

Rubinstein-Taybi Syndrome

DM1
FMR1
FMR2

Rett Syndrome

Down Syndrome

Figure 4. Nuclear function in cognitive disorder. Consolidation of long-term memory requires the regulation of gene expression. Active Rsk2
phosphorylates the transcription factor, CREB. P-CREB recruits the coactivator CREB binding protein (CBP) and promotes transcription of genes whose
promoters contain CRE sites. MeCP2 permanently represses expression of some genes that are methylated in CpG islands found in the promoters. Loss of
MeCP2 causes an aberrant increase in the dosage of some genes, usually genes that undergo imprinting. Expansion of trinucleotide repeat sequences in
genes changes local chromatin structure and influences RNA metabolism, leading to the dysregulation of several genes. Presence of an extra chromsome
(trisomy) results in pathological over-expression of potentially hundreds of genes.

nucleosomal proteins such as transcription factors. Thus,
normal expression of genes near the vicinity of DMPK, such as
the homeodomain protein Six5, is most likely disrupted (52).

The amounts of mature DMPK transcripts in the cytoplasm

are significantly reduced in DM1 (53). Interestingly, the mutated
DMPK transcripts, which possess CUG-repeat expansions, are
actually retained within the nucleus such that there is no
decrease in total DMPK1 mRNA expression in cells from DM1
patients (54). Retention of mutated DMPK transcripts can have
several adverse effects on RNA processing and translation. CUG-
rich DMPK transcripts can effectively titrate out CUG-binding
proteins involved in RNA metabolism, inhibiting their normal
function (55). In addition, the presence of excessive numbers of
DMPK transcripts can act as antisense RNAs by interfering with
the expression of other transcripts that contain CAG repeats
(56). Thus, expanded CTG repeats can directly affect the
expression of both neighboring genes in the chromosome
through chromatin restructuring, and many other genes by
inhibiting of RNA processing and translation. Therefore, the
molecular effects of the CTG expansion in DM1 are most likely
pleiotropic.

Haploinsufficiency of DMPK likely also impacts several

cell-signaling pathways. DMPK is a novel serine-threonine
protein kinase, with some similarity to the cAMP-dependent
protein kinases (57). The binding of Rac1, a GTPase associated
with the actin cytoskeleton, to DMPK stimulates the kinase
activity of DMPK in a GTP-dependent manner (57).
Furthermore, the serine-threonine kinase Raf-1 phosphorylates
and activates DMPK (57). Therefore, DMPK could potentially
integrate MAPK signals with other signaling pathways.

F

RAGILE

X M

ENTAL

R

ETARDATION

Fragile X syndrome is the most commonly inherited form of
mental retardation affecting approximately one in 4,000 males
(58). Male phenotypic characteristics include moderate
macrocephaly, long-narrow facial features with unusually large
ears, and general muscle hypotonia. Mental retardation severity
can range from moderate to severe, with most patients showing
IQs of approximately fifty. In females, Fragile X is seen in about
one in 7,000 live births; however, only approximately 30% of
those show any physical characteristics and all affected females
exhibit a milder mental handicap.

The Fragile X mental retardation syndrome is similar to other

inherited neurodegenerative disorders such as DM1 in that it is
effected by an abnormal expansion of repeated trinucleotide
sequences within the gene. Genetic analysis has revealed that the
trinucleotide expansion often does not appear all at once, but
rather occurs over several generations. Trinucleotide expansion
ultimately leads to decreased gene expression through mechanisms
that include aberrant methylation of DNA, and formation of
restrictive chromatin structure.

F

RAGILE

X M

ENTAL

R

ETARDATION

2

Expansion of a CCG repeat at Xq28 in the 5' untranslated region
of the FMR2 exon 1 at the Fragile-X E (FRAXE) site results in the
methylation and transcriptional disruption of FMR2 (Figure 4) (59,
60). Deficits in FMR2 differ considerably from FMR1 in affects on
behavior and the mechanism of cognitive disruption. FMR2 is a
rare disorder that occurs once in every 50,000–100,000 births.
FMR2 is associated with mild mental impairment (IQ of 50–85)
and primarily manifests as moderate learning difficulties and delay
in acquisition of language. A number of variable physical
abnormalities are observed, such as a long, narrow face, mild facial
hypoplasia, irregular teeth, thick lips, and nasal abnormalities. A
subset of FRAXE patients may exhibit behavioral disorders that
closely resemble attention deficit and hyperactivity disorder
(ADHD), and autism.

Produced through the disruption in the first exon of the

homologous murine FMR2 gene, the FMR2 knockout mouse has
revealed many interesting possibilities for a role for FMR2 in
development. Temporal regulation of wild-type FMR2 is seen
during embryogenesis where FMR2 is highly expressed for a brief
time in ganglionic eminences of the ventral telencephalon (61).
Beginning on E10.5, transcription of FMR2 coincides with the
differentiation of neuroblasts to various neuronal tissues (61).
Neuronal progenitor cells that migrate from the ventral
telencephalic region later develop in the cortices, with a large
fraction of the progenitor cells maturing into GABAergic
interneurons of the neocortex (61). Thus, in FMR2–/– mice,
inhibitory GABAergic neurotransmission may be disrupted.

FMR2-deficient mice show several interesting phenotypes

relevant to memory formation. FMR2 mice have deficits in
associative fear-conditioned learning, specifically hippocampus-
dependent contextual fear conditioning (61). In sharp contrast to
the observed deficits in hippocampus-dependent learning, NMDA-
dependent and -independent LTP was significantly enhanced, even
at saturating levels of high-frequency stimulation in hippocampal
area CA1 (61). These results are illustrative of a model for human
mental retardation where hippocampus-dependent learning is
inhibited, whereas induction and/or expression of hippocampal
LTP was enhanced. It is possible that the prominent role FMR2
plays in the development of GABAergic interneurons may underlie
the enhancement of hippocampal LTP and deficit in hippocampus-
dependent memory formation.

The true function of FMR2 is unknown; however, evidence

indicates that FMR2 is an activator of transcription. FMR2 is a
member of a protein family that includes AF4, LAF4, and
AF5Q31. The members of this family share high, regional amino-
acid similarity (20%-35% total amino acid identity) and localize to
the nucleus. Moreover, these proteins, including FMR2,
significantly augment transcription in both yeast and HeLa cells
(62). However, the mechanism of transcriptional activation
employed by the FMR2-like proteins is still unknown. It is

Genes and Proteins Involved in Cognition

383

October 2002

Volume 2, Issue 6

Review

384

?

?

CBP

P

Trisomy 21

CREB

Transcription

APP
DYRK1A
SOD1

Angelman Syndrome

Ubiquitin

ligase

NMDA
Receptor

Ca

2+

MEK

ERK

RSK2

Ras

DMPK

Rac

Spine:

- Maturation

- Development

- Morphology

Rubinstein-Taybi

Syndrome

Neurofibromatosis, MR

Coffin-Lowry

Syndrome

FMR2

Mytonic
Dystrophy

FMR1

Williams

Syndrome

Figure 5. Disruptions along the molecular cascade for memory formation lead to cognitive disorder. Memory formation begins with activation of
signaling pathways at the membrane of dendritic spines. The signaling cascade reaches the nucleus, where the activity of transcription factors is modulated,
resulting in changes in gene expression. Newly synthesized proteins cause long-term changes in cell function, such as the growth and maturation of new
dendritic spines.

possible that other members of the FMR2 family can compensate
for specific deficits in FMR2, which could explain the variability in
cognitive deficiencies seen in FRAXE.

D

ENDRITIC MORPHOLOGY IN COGNITIVE DEFICITS

Early studies of synapse morphology in the hippocampus

suggested that induction of synaptic plasticity in vitro and
memory formation in vivo are associated with increases in the
number of synapses (63, 64). Synapses in the mammalian CNS are
located at dendritic spines, and several recent studies have
indicated that dendritic spine morphology is very dynamic.
Changes in spine morphology are correlated with changes in
synaptic activity, such as occurs during induction of LTP in vitro

Genes and Proteins Involved in Cognition

385

October 2002

Volume 2, Issue 6

T

ABLE

1. S

UMMARY OF

D

ISEASES

A

FFECTING

H

UMAN

L

EARNING AND

M

EMORY

.

Human Mental

Gene Product

Potential Targets

Mouse Model

References

Retardation

Learning

LTP

Syndrome Defects

Change

Angelman Syndrome

Ubiquitin E6 ligase

p53 (tumor suppressor), others?

Yes

Yes

(2)

Neurofibromatosis

Neurofibromin 1 (NF1)

Ras/ERK

Yes

Yes

(11)

Adenylyl cyclase
Cytoskeleton

Coffin-Lowry

Ribosomal S6 Kinase 2

CREB

Yes

?

(17)

Syndrome

Ribosomal S6 protein

Down Syndrome

DS critical locus:

Dysregulation of genes

Yes

Yes

(20)

(Trisomy 21)

APP (A

)

on DS critical locus

DYRK1A
SOD1
KIRs

Rett Syndrome

Methyl-CpG Binding

Lack of transcriptional

No

No

(33, 40)

Protein 2 (MeCP2)

repression

Rubinstein-Taybi

CREB-Binding Protein

(CBP) CREB-mediated

Yes

?

(43, 47)

Syndrome

transcription

Myotonic Dystrophy

DM1-Protein Kinase

Chromatin structure

?

?

(49)

(DMPK)

RNA binding proteins
RNA interference

FMR2

FMR2 Protein

Unknown-gene expression

Yes

Yes

(61)

FMR1

FMR1 Protein

RNA targeting

Yes*

?

(77)

Protein synthesis
Spine structure

Williams Syndrome

WS critical locus:

Cytoskeleton

Yes

Yes

(72)

LIMK-1

Extracellular matrix

Elastin

Spine morphology

Syntaxin 1A
FKBP6
EIFH4

* - The design of the initial behavioral studies may have been flawed (78).

(65). Vital to dendritic remodeling is the actin cytoskeleton (66). In
the following sections, we review two diseases of human memory
formation that also affect the morphology of dendritic spines.

F

RAGILE

X M

ENTAL

R

ETARDATION

1

FMR1 is located at Xq27.3 at a unique site on the X chromosome
known as the Fragile X A site (FRAXA) (67). The polymorphic
CGG-repeat responsible for the loss of gene expression occurs at
the 5' UTR of FMR1 (Figure 4). Interestingly, if the repeat number
is between ~50 and 200, normal protein is produced and no
dysfunction is seen. However, if the expansion exceeds 200 CGG
repeats the disease will become manifest; in some cases, more than
1000 CGG repeats in FMR1 have been observed. The mutation of
FMR1 results in hypermethylation of the CGG expansion and of
the upstream CpG island in the promoter, leading to
transcriptional silencing of FMR1. The instability of the
trinucleotide expansion during embryogenesis often leads to
significant mosaicism in nearly 15% of patients with harboring at
least 200 CGG repeats.

FMR1 mRNA undergoes extensive alternative splicing and can

form up to twenty alternatively sliced proteins; however, only four
or five protein isoforms are detectable. Almost all FMR1 protein
(FMRP) consists of FMR1 isoform 7, which lacks exon 12. The
first solid evidence suggesting a specific role for FMRP in
cognition came from studies on brains of three fragile X patients
that showed an increase in dendritic spine density in the CNS
(68). The dendritic spines had a long, thin morphology, which
closely resembled the immature spines observed in developing
neurons. This suggested a role for FMR1 in neuronal maturation
or development, but it was not until the investigation of a mouse
model for FMR1 that putative mechanisms of FMRP action began
to emerge.

In 1994, a FMR1 knockout mouse was developed (69).

Although the animal model differs from the human cause of gene
disruption, absence of FMRP results in a phenotype resembling
that in FMR1 humans. This includes macroorchidism and deficits
in spatial learning and associative fear-conditioned learning (70).
There is an overall increase in the number of dendritic spines in
FMR1 mice (Figure 5). Dendritic spines of FMR1 mice are long
and thin, mimicking the human condition.

FMRP is a cytoplasmic RNA-binding protein that contains

three functional RNA binding motifs [two KH (heterogeneous
nuclear RNA-binding protein K homology) domains and an RGG
(Arg–Gly–Gly) box] and has been shown to associate with G
quartets present in mRNA in vivo (71). There is some evidence
that FMRP may chaperone mRNA from the nucleus to the synapse
(Figure 5). Another possible role for FMR1 is in synaptic
maturation (Figure 5). The increase of long, thin dendritic
processes and a higher density of dendritic spines observed in the
brains of Fmr1–/– mice and humans with FMR1 suggest that the
lack of mature synapses underlies the observed cognitive deficits.

The appearance of immature spines may not be due to a
developmental derangement, but rather due to changes in protein
expression under the transcriptional control of FMRP. This theory
is supported by two lines of evidence: 1) The synaptic immaturity
seen in FMR1 knockout mice and in human patients resembles
that which can be caused by sensory deprivation and, 2) FMR1
translocates to the areas surrounding synapses following
stimulation of metabotropic glutamate receptors. A greater
understanding of the pathogenesis of the Fragile X syndrome will
unquestionably be attained through the analysis of the function of
FMRP.

W

ILLIAMS

S

YNDROME

Williams Syndrome (WS) is a relatively common disorder,
occurring once in 20,000 live births (72). WS patients exhibit an
interesting idiosyncratic social behavioral syndrome—they are
overly friendly. Behavioral studies of WS patients show that they
manifest an abnormal positive bias toward unknown individuals
(73); they have been described as “never having met a stranger,”
treating even people that they have just met with great familiarity.
They also exhibit spatio-visual processing deficits, highly acute
hearing, and mild-to-severe mental retardation. WS arises from
deletions in chromosome 7 that typically include multiple genes.
Given the complex behavioral manifestations in WS patients,
Williams Syndrome provides an interesting example of genetic
contributions to complex social behaviors.

WS is associated with a 1.5 Mb deletion in chromosome

7q11.23 (74). Several genes have been identified within the WS
locus (72) including LIM Kinase 1 (LIMK-1) (75, 76). LIMK-1 is a
target of the Rac and Rho small GTPases, and PKC signals that
control cytoskeletal organization (Figure 5). LIMK-1 exerts its
effects through phosphorylating and inhibiting Actin
Depolymerization Factor (ADF)/cofilin. ADF/cofilin normally
binds directly to actin and promotes its depolymerization. Thus,
the LIMK-1 pathway is one of the specific mechanisms whereby
the Rho system regulates cytoskeletal structure.

LIMK-1 homozygous knockout mice, as expected, have

alterations in actin microfilaments due to derangements of actin
turnover. They also manifest altered dendritic spine morphology at
Schaffer collateral synapses in the hippocampus. Specifically, they
have fewer actin microfilaments than the normally actin-dense
spines, and the dendritic spines in LIMK-1 knockout mice lack the
normal bulbous ending that dendritic spines exhibit. There are no
apparent alterations in synaptic number or baseline synaptic
function, however. Like FMR2 knockout mice, LIMK-1 knockouts
exhibit LTP that saturates at a higher level than that seen in
control mice—that is, a higher maximal level of potentiation is
achieved with repetitive LTP-inducing stimulation. This alteration
in synaptic plasticity is associated with impaired learning as well.
Specifically, LIMK-1 knockouts show a decrease in their capacity
to “unlearn” the location of a hidden platform in a Morris Water

Review

386

Maze task, once they have learned that a platform is associated
with a particular location. This is assessed using a platform
reversal variation of the Water Maze, where the hidden platform is
moved to a new location after the animal has been repeatedly
trained with the platform in one place. The effects on LTP and
dendritic spine morphology in the LIMK-1 knockout mouse
suggest a possible basis for the cognitive effects in WS. They also
point to the growing understanding of the importance of
morphological regulation in learning and synaptic plasticity,
including, apparently, those processes occurring in the human
CNS.

C

ONCLUSIONS

A great deal of progress has been made in the last decade in
understanding the molecular basis for deficiencies in human
memory formation. Much of this progress has been made using
animal models where normal gene expression has been disrupted.
Interpretation of results from knock-out animal models is difficult,
as one cannot rule out the possibility that expression of the altered
gene may not be directly involved in memory formation, but
rather is involved in development of the relevant neural pathways.
Most of the mutations we describe do not lead to gross
morphological changes in the CNS in the human or mouse. Mouse
studies, where available, indicate that baseline synaptic
transmission in many of the mutations is normal as well. These
observations are consistent with an ongoing need for newly
synthesized gene products in cognitive processing. Additionally, in
the case of the ERK–CREB–CBP pathway, there is direct evidence

from animal studies that acute inhibition of the signal in adults is
sufficient to cause learning deficiencies. These types of
considerations suggest a rethinking of our outlook on human
learning disorders from the traditional view of them as
developmental problems to a new view of them as cognitive
deficiencies. This change in outlook has been precipitated by new
and ongoing discoveries concerning the basic signal transduction
processes underlying learning and memory.

Arguably, the holy grail quest of neuroscience research is

unlocking the mystery of human cognition. Initial studies of brain
structure proved intimidating; how could one find the needle that
is human cognition, when it lay buried in a haystack of 1010
neurons with 1013 connections? Studies of brain lesions
elucidated where in the brain memories were formed and stored,
but shed little light as to the mechanisms underlying its formation.
It was not until the molecular genetics revolution that serious
progress was made in beginning to dissect the cellular and
molecular basis of human cognition. Perhaps the most striking
observation made concerning the molecular basis of human
cognitive deficiency is that no cellular process is invulnerable to
disruption. Deficits in human cognition arise from cellular defects
in receptor-mediated second-messenger signaling pathways
through disruptions in chromatin structure (Figure 5). In fact, we
now live in a world where observations from knockout mice are
utilized to understand the associated condition in “knockout”
humans. With all the progress that has been made understanding
cognition and the basis for deficits, the next wave of research
should begin to shed light on how to alleviate, or possibly cure
some of these debilitating diseases.

Genes and Proteins Involved in Cognition

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October 2002

Volume 2, Issue 6

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J. David Sweatt, PhD, is a Professor in the Division of Neuroscience and a member of the Mental Retardation Research Center at Baylor
College of Medicine. His research focuses on basic mechanisms of learning and memory, mental retardation syndromes and Alzheimer’s
disease. Edwin J. Weeber, PhD, is an Instructor at Baylor College of Medicine studying signal transduction mechanisms involved in
learning and memory. Jonathan M. Levenson, PhD, is a Post-doctoral Fellow in Dr. Sweatt’s laboratory at Baylor College of Medicine
studying the molecular genetics of long-term memory formation in the hippocampus. Address correspondence to JDS. E-mail
[e-mail]