Molecular
Genetics
of Human
Cognition
n intimate relationship exists between our capacity for
Alearning 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.
Edwin J. Weeber, Jonathan M. Levenson, J. David Sweatt
Division of Neuroscience, Baylor College of Medicine
1 Baylor Plaza, Houston, TX 77030
376
Genes and Proteins Involved in Cognition
INTRODUCTION
Cognition can be defined as the active
intellectual processes through which
information is obtained, transformed,
stored, retrieved, and used by the
CREB-mediated
brain. The ability to form long-lasting
Ca2+
Signal Transduction Cascades transcription
memories and to retrieve these
Long lasting changes in synaptic efficacy
memories when necessary is the axis
- Altered electrical properties of membrane
upon which human cognitive ability
- Increased glutamate receptor expression
revolves. Memory formation not only
- Changes in synaptic morphology
- Increased number of synapses
defines who we are as a species in our
Protein synthesis
capacity for learning, but our personal
memories and experiences help to
define who we are as individuals. It
Figure 1. Processes involved in memory formation. Formation of
should be recognized that the capacity for this basic, intrinsic
memory is a complex process that requires several aspects of cell function.
ability to form new memories is ultimately genetic in origin. This
Memory formation begins at the plasma membrane. Upon activation,
becomes extremely evident when a genetic aberration causes a NMDA-type glutamate receptors allow Ca2+ to flow into the cell. The Ca2+
flux activates several second-messenger signaling cascades. Ultimately, these
disruption in the capacity for memory formation and manifests in
signaling processes activate the transcription factor CREB, which leads to
an individual as a pronounced cognitive deficit.
the modulation of several genes required for consolidation of long-term
We have reached a point where clinical and basic science
memory. Translation of newly synthesized mRNAs leads to production of
research have converged and provide us insight into the molecular
proteins required to affect long-term changes in neuronal physiology.
basis of human cognition. Only recently have neuroscience
researchers begun to solve any of the mysteries surrounding leads to the release of glutamate, which activates a host of
proteins and signaling pathways that underlie the formation of glutamate receptors on the postsynaptic spine (Figure 1).
lasting memory in the mammalian brain. In parallel, clinical Glutamate receptors are generally divided into two broad
research has identified many genes responsible for human learning categories: ionotropic and metabotropic. Ionotropic receptors are
disorders. Thus, we are at a point where new hypotheses can be ligand-gated channels that can depolarize the membrane [i.e., -
formulated concerning the molecular mechanisms that underlie amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and
human mental retardation syndromes. Additionally, the kainate subtypes] or allow calcium influx [i.e., N-methyl-D-
identification of specific genes and their products in human aspartate (NMDA) receptors]. Metabotropic receptors are coupled
disorders that are associated with mental retardation has greatly to intracellular second messenger cascades. High-frequency
facilitated our understanding the basic mechanisms involved in stimulation results in a large postsynaptic depolarization, which
the formation of human memories. allows for activation of the NMDA-subtype of ionotropic glutamate
The following review examines the genetic causes and receptors leading to Ca2+ influx into the spine. Moreover, the
biochemical consequences of several recently identified disorders attendant high levels of glutamate allow for activation of
that result in a disruption of human cognitive ability. Although our metabotropic glutamate receptors, which are coupled to the
understanding of many of these disorders is incomplete and still phospholipase C (PLC) pathway. The increase in intracellular Ca2+
under intense investigation, we discuss the implications of the and the activation of metabotropic glutamate receptors in the
emerging molecular basis of these disorders on our current spine leads to activation of a number of postsynaptic protein-
understanding of learning and memory mechanisms. One focus of kinase signaling pathways, including the Ca2+-calmodulin kinase
our review will be how new, genetically engineered mouse models II (CaMKII), cAMP-dependent protein kinase (PKA), protein
of human mental retardation syndromes have given us insight into kinase C (PKC) pathways, and the Ras pathway. One downstream
the molecular biology of human learning disorders. 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
MEMORY FORMATION: A MOLECULAR PRIMER
ribosomal S6-kinase 2 (RSK2), which in turn phosphorylates the
Much progress has been made in the last decade toward transcription factor cAMP response-element (CRE) binding protein
understanding the molecular blueprint for long-term memory (CREB). CREB recruits a number of transcriptional coactivators,
formation in the mammalian brain. Long-term memory formation including CREB binding protein (CBP), and initiates a wave of
begins at the plasma membrane of neurons, at synapses located on transcription that is vital for the consolidation of long-term
dendritic spines. High frequency presynaptic activity at these sites memory. Newly synthesized transcripts must be transported out of
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Glutamate
Review
the nucleus and translated into functional proteins, which effect abnormalities and brain-specific imprinting of Ube3a observed in
lasting changes in synaptic strength by altering the electrical humans (3, 6, 7). The mouse model developed by Jiang et al. has
properties of the membrane, increasing the responsiveness to provided a variety of information regarding the neural basis of the
neurotransmitter, and even changing the number and size of cognitive defects caused by AS (7). Initial studies of mice that do
synapses. not express maternal Ube3a showed severe impairments in
The formation of memory, thus, depends upon the hippocampal memory formation (7). Most notably, there is a
coordination of numerous cellular processes. A consequence of the deficit in a learning paradigm that involves hippocampus-
complexity of memory formation however, is that disruption of dependent contextual fear conditioning. In addition, maintenance
one, or a few of the molecular steps involved can be deleterious. of long-term synaptic plasticity in hippocampal area CA1 in vitro
For example, deficits in human memory formation (i.e., mental is disrupted in Ube3a / mice (7). Thus, current research using
retardation) are caused by specific defects in the molecular this mouse model focuses on the molecules required for
pathways responsible for memory formation. In the sections that hippocampal synaptic plasticity. The results from murine gene-
follow, we will explore the molecular basis of some molecular knockout studies provide a link between hippocampal synaptic
defects along this pathway that result in cognitive deficits in plasticity in vitro and formation of hippocampus-dependent
humans. memory in vivo, and suggest that the expression of synaptic
plasticity, as measured by LTP formation, underlies human
hippocampus-dependent memory formation.
CELL SIGNALING: DEFECTS IN INFORMATION-FLOW
FROM THE MEMBRANE TO THE NUCLEUS
NEUROFIBROMATOSIS
Recent work has shown that a number of signaling cascades must
be activated to successfully form long-term memories. In One of the most common single-gene disorders causing
retrospect, it is not surprising then, that a number of deficits in cognitive disorders in humans is Neurofibromatosis type 1
human cognition arise from derangements in the functioning of (NF1), which affects approximately one in 4,000 individuals.
these signaling pathways vital to the formation of memory. The predominant phenotypic characteristic of NF1 is the
development of benign neurofibromas of the peripheral
ANGELMAN SYNDROME nervous system. Other clinical manifestations include
malignant tumors (gliomas or malignant peripheral nerve
Angelman Syndrome (AS) is a severe form of mental retardation sheath tumors), skin discoloration, and skeletal dysplasia. NF1
that occurs in one of every 15,000 20,000 births. AS is usually leads to varying levels of mild cognitive impairment in
accompanied by epilepsy, a puppet-like gait, dysmorphic facial 40 65% of patients (8). The heterogeneity of NF1 gene
features, a happy disposition with bouts of inappropriate laughter, mutations is thought to contribute to its lack of complete
hyperactivity, sleep disorders, and lack of speech (1, 2). penetrance for various phenotypes, including cognitive
In 1997, the gene responsible for AS was identified as the disruption (9).
ubiquitin-protein ligase, Ube3a (3, 4). An unusual characteristic of The product of the NF1 gene, neurofibromin, is highly
this defect is that the Ube3a locus undergoes imprinting, whereby expressed in brain during embryogenesis, and in adults it is
only the maternal allele is active in specific tissues. The paternal primarily expressed in pyramidal and Purkinje neurons, Schwann
silencing of the Ube3a gene occurs in a brain region-specific cells, and oligodendrocytes. NF1 mRNA undergoes alternative
manner; the maternal allele is active almost exclusively in the splicing resulting in four different protein isoforms (type I-IV);
hippocampus and cerebellum (5). The most common genetic however, the predominant neuronal forms are produced through
defect leading to AS is an ~4 Mb maternal deletion in alternative splicing of exon 23a, resulting in type I (NF1-I,
chromosomal region 15q11 13 causing an absence of Ube3a exclusion of exon 23a) or type II (NF1-II, inclusion of exon 23a)
expression in the maternally imprinted brain regions. Ube3a codes protein (10).
for an E6-AP ubiquitin ligase, an enzyme involved in the Exon 23a contributes to the regulation of GAP [guanosine
ubiquitin-proteasome pathway. Ubiquitination targets proteins for triphosphatase (GTPase) Activating Protein] activity intrinsic to
degradation through the proteasome pathway. However, E6-AP NF1 (Figure 2). This domain (including the GAP) is important for
ubiquitin-ligase chooses its substrates very selectively and the four interactions of NF1 with Ras (10), a low molecular weight GTPase
identified E6-AP substrates have shed little light on the possible that acts as a critical relay in signal transduction by cycling
molecular mechanisms underlying the human AS mental between an active conformational state (Ras·GTP) and an inactive
retardation state. The development of mouse models for AS has state (Ras·GDP) (Figure 2A). The GAP activity of NF1 promotes
increased our understanding of the genetic alterations and the hydrolysis of GTP and the formation of Ras·GDP, thus
physiological consequences underlying this disorder. inhibiting Ras activity. Guanine nucleotide exchange factors
There are two mouse models for AS which replicate the (GEFs) counterbalance the effects of GAP proteins by catalyzing
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Genes and Proteins Involved in Cognition
Figure 2. Signaling pathways implicated in human memory formation.
A 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
NF1
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 domain
Inactive Active
(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
Ras Ras
activates the DM1-associated protein kinase (DMPK) involved in myotonic
dystrophy. RSK2 is activated by ERK, and regulates gene transcription. CLS
GDP GTP
is due to disruption of RSK2.
GEF
GTP COFFIN-LOWRY SYNDROME
GDP
B
Coffin-Lowry Syndrome (CLS) is an X chromosome-linked
Ras
disorder. Affected males with CLS are characterized by an
PKA
abnormal gait, facial abnormalities (protruding forehead, wide
noses, and irregular teeth), skeletal abnormalities (osteopenia,
PKC
Rap1
short stature, and muscular hypodevelopment) and severe mental
Raf-1
retardation (13, 14). As with other X-linked disorders,
heterozygous females exhibit similar but much less severe
B-Raf
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
DMPK MEK
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
ERK
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).
CREB Elk-1
RSK2
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
the exchange of GDP for GTP, leading to increased amounts of activates of Rsk2, which is responsible for PKA-dependent CREB
Ras·GTP. Therefore, loss of NF1-dependent inhibition of Ras could activation in the hippocampus (Figure 2B).
lead to the learning deficits seen in NF1 (11). Dufresne et al. have produced a viable, Coffin-Lowry mouse
In a series of elegant studies, Costa et al. investigated the role model through the disruption of Rsk2 (17). Rsk2 mutant mice
of Ras in the cognitive disruption of NF1 (12). NF1 heterozygous exhibit deficits in motor learning and coordination, and have
knockout animals, which show a deficit in spatial learning, were severe deficits in spatial learning. However, much of what can be
crossed with animals deficient in Ras activity. Remarkably, the inferred about the role of Rsk2 in cognitive function has come
genetic diminishment of Ras activity was sufficient to rescue the from studying the activity of ERK1, ERK2, and CREB in synaptic
spatial learning deficit observed in the NF1 heterozygous mice. plasticity and memory formation. The requirement for the ERK
Additionally, learning deficits were rescued in NF1-heterozygous and CREB in synaptic plasticity and formation and consolidation
animals treated with a farnesyltransferase inhibitor, suggwsting of long-term memories is well established. Thus, molecular
that hyperactivation of the Ras pathway is the likely cause of components of memory formation up- and downstream of Rsk2
learning deficiencies in NF1-deficient mice and patients with NF1. are involved in mammalian cognition. Yet, many questions still
The question remains: what are the downstream targets of exist about the role(s) of Rsk2 in neuronal function and the mental
Ras hyperactivation that lead to cognitive disruption? Ras regulates aberrations seen in CLS. For example, evidence implicates Rsk2-
the Raf ERK cascade in a variety of cells, including hippocampal mediated phosphorylation of SOS, a GEF for Ras, as a possible
neurons (Figure 2B). Therefore, it is likely that the ultimate mechanism for negative-feedback regulation of the
consequence of hyperactivation of the Ras signal transduction Ras MEK MAPK pathway (18). Further investigation of the
cascade lies in the dysregulation of one or more ERK-regulated mechanisms underlying deficits in synaptic plasticity and memory
transcription factors, including CREB, Elk-1 and c-Myc. formation in CLS-model mice will be necessary.
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Review
COGNITIVE DISRUPTION AT THE NUCLEUS
and are required for induction of hippocampal LTP in vitro (25,
26). In mouse models, overexpression of SOD, as would occur in
Changes in cellular physiology due to the direct action of various DS, leads to decreases in ambient levels of superoxide and impairs
second messengers and signaling pathways are short-lived at best. induction of hippocampal LTP in vitro and hippocampus-
Long-term changes in cell function are usually effected through dependent long-term memory formation in vivo (27).
changes in expression of one or more genes. Thus, ultimately gene DYRK1A, the human homolog of the Drosophila Minibrain
expression is necessary for the integration of external signals with kinase, is also well studied. DYRK1A is located in the DS-critical
long-term internal cellular function. It is not surprising that many region of chromosome 21 and is expressed in several structures of
diseases of cognition are due to derangement of nuclear function. the adult CNS including the cortex, hippocampus and cerebellum
(28). Dyrk1A expression is significantly elevated in the CNS
DOWN SYNDROME: ABERRANT GENE DOSAGE during development in DS humans and in a mouse model for DS,
Ts65Dn (29). Transgenic mice that overexpress Dyrk1A
First described by John Langdon Down in 1866, Down Syndrome (TgDyrk1A) display several behavioral abnormalities that are
(DS) is the most common form of mental retardation. DS occurs in similar to those seen in DS. Specifically, TgDyrk1A mice are
one out of 800 live births, and accounts for nearly 30% of delayed in their acquisition of mature locomotor skills and have
moderate to severe mental retardation. There are a number of deficits in spatial learning (30).
stereotypical physical attributes associated with DS including short Human Ts21 neurons appear to have significantly different
neck, short broad hands, flat nasal bridge, and narrow palate. IQs passive electrical properties from normal diploid neurons (20).
of DS patients range from 40 70, depending on the severity of the Ts21 neurons are more excitable at rest, and show dramatically
illness. Individuals with DS display a pronounced delay in the different rates of action potential depolarization and repolarization
development of language, and exhibit deficits in various forms of (20). Neurons isolated from Ts16 mice, the other mouse model for
short-term and spatial memory. There is an increased risk for early DS, also have abnormal, passive electrical properties; however, the
development of Alzheimer dementia, which usually occurs around differences observed do not exactly replicate those found in the
age thirty-five. human disease (20). Not surprisingly, there are several genes on
The molecular basis for DS is the presence of an extra copy of human chromosome 21 involved in the regulation of neuronal
chromosome 21, referred to as trisomy 21 (Ts21). Chromosome excitability, including the inward-rectifying K+ channels
21 is 45 Mb long and contains 303 genes. A region of ~5 Mb of Kcnj6/Kir3.2, Kcnj15/Kir4.2, and Kcne1 (20).
chromosome 21 has been implicated in the development of mental
retardation in DS patients (19), and within this critical region lie RETT SYNDROME
several genes that may affect memory formation (20).
Overexpression of genes from this locus is thought to interfere Andreas Rett, an Austrian pediatrician, first described Rett
with their normal regulation and to lead to the cognitive deficit in syndrome (RS) in 1966 (31). In the United States, RS did not gain
DS (21). Two mouse models with trisomy have been generated major attention until 1983, when it was further characterized by
(Ts16, Ts65Dn), both of which mimic most of the DS human Hagberg et al. (32). RS is an inherited, X-linked disease that afflicts
phenotype including severe memory impairments (20). In the about one in 15,000 females by ages 2 18 years of age, and is
following sections we will briefly review some of the more estimated to be the second leading cause of mental retardation in
prominent genes in this region. women, behind DS (33). Development during the first six months
Perhaps the most notorious gene the critical region of of life is normal in RS patients, with symptoms appearing between
chromosome 21 encodes is the amyloid precursor protein (APP). three months to three years. The trademark of RS is display of
The APP-derived peptide known as amyloid beta peptide (A ) is continuous, stereotypical hand movements, such as wringing,
one of the primary components of the plaques found in the brains washing, clapping or patting, which appear after the loss of
of Alzheimer s disease patients (22). Mice that overexpress A have purposeful hand movement. Other signs of RS include decreased
deficits in LTP induction and memory formation (23). Recently, growth (including microcephaly), abnormal respiration, gait ataxia,
Dineley et al. (24) showed that A can activate the ERK signaling autism, seizures and other neurologic dysfunctions. Several
cascade through 7-nicotinic acetylcholine receptors. Moreover, mapping studies narrowed the location of the putative RS locus to
A -dependent dysregulation of ERK signals leads to aberrant Xq28 (34), and in a percentage of patients, a mutation of the
increases in phosphorylation of CREB (24). As mentioned above, methyl CpG binding protein 2 (MeCP2), whose gene is located in
the ERK CREB signaling pathway is essential in the formation of Xq28, is correlated with Rett syndrome (35).
long-term memories in a number of different organisms. MeCP2 functionally connects DNA methylation to gene
Another gene present on chromosome 21 implicated in silencing (Figure 3). DNA methyltransferases catalyze the
memory formation is the Cu2+/Zn2+ superoxide dismutase methylation of cytosine at position 5 using S-adenosylmethionine
(SOD1) gene. Superoxides can potentiate synaptic transmission as a methyl donor. Methylation usually occurs at CpG (cytosine,
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Genes and Proteins Involved in Cognition
attempts to create MeCP2-deficient mice have succeeded (38, 39).
Promoter
These mice display some of the characteristics of RS including
reduced brain and body size, tremors, hypoactivity, and irregular
CH3 CH3 CH3 CH3
MeT
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
CpG island
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
Sin3a HDACs
MeCP2
anxiety, and display some repetitive forelimb movement (40).
CH3 CH3 CH3 CH3
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.
RUBINSTEIN-TAYBI SYNDROME
Sin3a
HDACs
Described by Rubinstein and Taybi in 1963 (41), Rubinstein-Taybi
MeCP2
Syndrome (RTS) occurs approximately once in every 125,000 live
CH3 CH3 CH3 CH3
Transcription blocked 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
Figure 3. Repression of transcription via methylation. DNA
to chromosome 16p13.3, which contains the gene for the
methyltransferases (MeT) catalyze the methylation of cytosine, producing
5'-methylcytosine (5mC). Most cytosine methylations occur in cytosine transcriptional coactivator CREB-binding protein (CBP) (43).
phosphorylated guanine (CpG) dinucleotide repeats (islands). The
Subsequent studies have shown that RTS patients have a variety of
transcriptional repressor, methyl-CpG binding protein 2 (MeCP2), binds to
mutations in CBP, including point mutations and 5'- or 3'-
5mCpG and recruits histone deacetylases (HDAC) and corepressors, such
deletions (44). It should be noted that patients are typically
as Sin3a. The activity of this protein complex causes a change in chromatin
heterozygous for a mutation in CBP, suggesting that RTS is due to
structure such that transcription is blocked. Rett syndrome is believed to
be caused by disruption of MeCP2. either haploinsufficiency or a dominant-negative effect (43).
Homozygous mutations of CBP are likely embryonic lethal in
phosphorylated guanine) dinucleotides. The distribution of CpG humans. Homozygous CBP-deficient mutant mice die in the early
in the genome is not random; most CpG is found in repeating embryonic stage (E10.5 E12.5), apparently as a result of massive
sequences and in CpG-enriched areas (islands). Interestingly, CpG hemorrhage caused by defective blood vessel formation in the
islands are most commonly found in the promoter region of genes. CNS, and exhibit developmental abnormalities as well as delays in
Once methylated, 5mCpG is bound by MeCP2, which then both primitive and definitive hematopoiesis.
recruits a complex of proteins including histone deacetylases and CBP is important in linking CREB activation to gene
transcriptional corepressors such as Sin3A (36). Ultimately, the transcription. The transcription factor CREB lies dormant in the
histones associated with the 5mCpG become hypoacetylated, nucleus until activated by phosphorylation. Once activated,
promoting tight association between the DNA and the histones phospho-CREB (P-CREB) recruits CBP and binds to CREs within
and resulting the formation of a stable, transcriptionally-repressive the DNA (Figure 4). CBP is thought to acetylate histones
chromatin complex. associated with the CRE, disrupting the chromatin within the
The role that MeCP2 might play in the memory deficits promoter and facilitating the binding of the RNA polymerase II
observed in RS is still unclear. DNA methylation is involved in holoenzyme (45). Therefore, an increase in CREB-mediated
genome imprinting and dosage-compensation. Therefore, MeCP2 transcription is associated with an increase in histone acetylation,
would be predicted to play a prominent role during development. especially histones located near CREs. Indeed, several studies
Indeed, early attempts to create mice lacking MeCP2 resulted in indicate that histone acetylation accompanies increases in CREB-
embryonic lethality (37). However, RS is a progressive disease that dependent transcription (45).
does not result in symptoms until early childhood. More recent CREB plays an important role in consolidation of long-term
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Review
Rubinstein-Taybi Syndrome
Nucleus
CBP
CREB
RSK2
ERK
Trinucleotide Repeat
MeCP2
Trisomy 21
Rett Syndrome
DM1
FMR1
FMR2
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.
memory. If CBP is vital for CREB-mediated transcriptional most common form of muscular dystrophy, myotonic dystrophy
regulation, it follows that CBP would also be important for long- (DM1) occurs once in every 8,000 live births (48). Symptoms
term memory formation. Therefore, mutations in CBP or usually begin to appear in adulthood, and include mild mental
disruption of CBP expression would be predicted to lead to retardation, myotonia, abnormal cardiac conduction,
impairments in memory formation, such as those seen in RTS. hypersomnia, cataracts, insulin-dependent diabetes, and
Two different strains of mice with mutated CBP alleles have been testicular atrophy, and premature balding in men. Congenital
studied (46, 47). The first strain, which contains a null mutation cases of DM1 are more pronounced than cases of DM2, and
leading to haploinsufficiency, had no memory impairments (46). characteristics include severe mental retardation, hypotonia,
However, the second strain, which was heterozygous for a facial dysplegia, inability to feed and respiratory problems. We
dominant-negative mutant form of CBP that possessed only the will focus on the molecular basis of the cognitive impairments
CREB binding domain (CBPDN), mimicked nearly all aspects of associated with DM1.
RTS (47). Specifically, CBPDN mice had altered facial features and DM1 is an inherited, autosomal dominant disease that has
stunted growth (47). Moreover, CBPDN mice had dramatic deficits been mapped to chromosome 19q13.2 13.3 (49). Subsequent
in long-term memory formation, with normal short-term memory studies identified DM1-associated protein kinase (DMPK) as the
(47), suggesting that RTS is caused by a dominant-negative gene mutated in DM1. The exact mutation responsible for DM1
mutation in one allele of CBP. Furthermore, these results was determined to be an unstable CTG repeat located in the 3'-
demonstrate that CBP plays a critical role in the consolidation of untranslated region (UTR) of DMPK (Figure 4) (49). DM1 is one
long-term memory. The histone-acetyl transferase (HAT) activity member of a class of cognitive diseases whose basis lies in
possessed by CBP, was absent from the CBPDN mice, might expansion of trinucleotide repeats (see FMR1 and FMR2 below).
specifically underlie the deficits in consolidation of long-term In the general populace, DMPK contains from 5 27 CTG
memory. If the HAT activity is indeed the critical factor underlying repeats, whereas in DM1 thousands of repeats can be present.
RTS, then this suggests that histone deacetylase inhibitors might The molecular basis of DM1 involves the dysregulation of a
be able to treat this disease. whole host of genes. Expansion of CTG repeats in the 3'-UTR of
DMPK can have several consequences on cellular function. CTG
MYOTONIC DYSTROPHY repeats favor nucleosome assembly and a condensed chromatin
structure (50). Indeed, experimental evidence indicates that in
Muscular dystrophy describes a class of diseases whose ultimate DM1, the CTG repeats in DMPK favor condensed chromatin
pathology is striated muscle wasting and eventual death. The (51). Condensed DNA is not accessible for binding by non-
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Genes and Proteins Involved in Cognition
FRAGILE X MENTAL RETARDATION 2
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). Expansion of a CCG repeat at Xq28 in the 5' untranslated region
The amounts of mature DMPK transcripts in the cytoplasm of the FMR2 exon 1 at the Fragile-X E (FRAXE) site results in the
are significantly reduced in DM1 (53). Interestingly, the mutated methylation and transcriptional disruption of FMR2 (Figure 4) (59,
DMPK transcripts, which possess CUG-repeat expansions, are 60). Deficits in FMR2 differ considerably from FMR1 in affects on
actually retained within the nucleus such that there is no behavior and the mechanism of cognitive disruption. FMR2 is a
decrease in total DMPK1 mRNA expression in cells from DM1 rare disorder that occurs once in every 50,000 100,000 births.
patients (54). Retention of mutated DMPK transcripts can have FMR2 is associated with mild mental impairment (IQ of 50 85)
several adverse effects on RNA processing and translation. CUG- and primarily manifests as moderate learning difficulties and delay
rich DMPK transcripts can effectively titrate out CUG-binding in acquisition of language. A number of variable physical
proteins involved in RNA metabolism, inhibiting their normal abnormalities are observed, such as a long, narrow face, mild facial
function (55). In addition, the presence of excessive numbers of hypoplasia, irregular teeth, thick lips, and nasal abnormalities. A
DMPK transcripts can act as antisense RNAs by interfering with subset of FRAXE patients may exhibit behavioral disorders that
the expression of other transcripts that contain CAG repeats closely resemble attention deficit and hyperactivity disorder
(56). Thus, expanded CTG repeats can directly affect the (ADHD), and autism.
expression of both neighboring genes in the chromosome Produced through the disruption in the first exon of the
through chromatin restructuring, and many other genes by homologous murine FMR2 gene, the FMR2 knockout mouse has
inhibiting of RNA processing and translation. Therefore, the revealed many interesting possibilities for a role for FMR2 in
molecular effects of the CTG expansion in DM1 are most likely development. Temporal regulation of wild-type FMR2 is seen
pleiotropic. during embryogenesis where FMR2 is highly expressed for a brief
Haploinsufficiency of DMPK likely also impacts several time in ganglionic eminences of the ventral telencephalon (61).
cell-signaling pathways. DMPK is a novel serine-threonine Beginning on E10.5, transcription of FMR2 coincides with the
protein kinase, with some similarity to the cAMP-dependent differentiation of neuroblasts to various neuronal tissues (61).
protein kinases (57). The binding of Rac1, a GTPase associated Neuronal progenitor cells that migrate from the ventral
with the actin cytoskeleton, to DMPK stimulates the kinase telencephalic region later develop in the cortices, with a large
activity of DMPK in a GTP-dependent manner (57). fraction of the progenitor cells maturing into GABAergic
Furthermore, the serine-threonine kinase Raf-1 phosphorylates interneurons of the neocortex (61). Thus, in FMR2 / mice,
and activates DMPK (57). Therefore, DMPK could potentially inhibitory GABAergic neurotransmission may be disrupted.
integrate MAPK signals with other signaling pathways. FMR2-deficient mice show several interesting phenotypes
relevant to memory formation. FMR2 mice have deficits in
associative fear-conditioned learning, specifically hippocampus-
FRAGILE X MENTAL RETARDATION
dependent contextual fear conditioning (61). In sharp contrast to
Fragile X syndrome is the most commonly inherited form of the observed deficits in hippocampus-dependent learning, NMDA-
mental retardation affecting approximately one in 4,000 males dependent and -independent LTP was significantly enhanced, even
(58). Male phenotypic characteristics include moderate at saturating levels of high-frequency stimulation in hippocampal
macrocephaly, long-narrow facial features with unusually large area CA1 (61). These results are illustrative of a model for human
ears, and general muscle hypotonia. Mental retardation severity mental retardation where hippocampus-dependent learning is
can range from moderate to severe, with most patients showing inhibited, whereas induction and/or expression of hippocampal
IQs of approximately fifty. In females, Fragile X is seen in about LTP was enhanced. It is possible that the prominent role FMR2
one in 7,000 live births; however, only approximately 30% of plays in the development of GABAergic interneurons may underlie
those show any physical characteristics and all affected females the enhancement of hippocampal LTP and deficit in hippocampus-
exhibit a milder mental handicap. dependent memory formation.
The Fragile X mental retardation syndrome is similar to other The true function of FMR2 is unknown; however, evidence
inherited neurodegenerative disorders such as DM1 in that it is indicates that FMR2 is an activator of transcription. FMR2 is a
effected by an abnormal expansion of repeated trinucleotide member of a protein family that includes AF4, LAF4, and
sequences within the gene. Genetic analysis has revealed that the AF5Q31. The members of this family share high, regional amino-
trinucleotide expansion often does not appear all at once, but acid similarity (20%-35% total amino acid identity) and localize to
rather occurs over several generations. Trinucleotide expansion the nucleus. Moreover, these proteins, including FMR2,
ultimately leads to decreased gene expression through mechanisms significantly augment transcription in both yeast and HeLa cells
that include aberrant methylation of DNA, and formation of (62). However, the mechanism of transcriptional activation
restrictive chromatin structure. employed by the FMR2-like proteins is still unknown. It is
October 2002
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Review
FMR2
Rubinstein-Taybi
Syndrome
Transcription
CBP
P
CREB
Trisomy 21
Angelman Syndrome
APP
DYRK1A
SOD1
Ubiquitin
ligase
?
NMDA
Coffin-Lowry
Ca2+
Receptor Syndrome
MEK ERK RSK2
Ras
?
DMPK
FMR1
Mytonic
Dystrophy
Rac
Neurofibromatosis, MR
Williams
Syndrome
Spine: - Maturation
- Development
- Morphology
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.
384
Genes and Proteins Involved in Cognition
TABLE 1. SUMMARY OF DISEASES AFFECTING HUMAN LEARNING AND MEMORY.
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).
possible that other members of the FMR2 family can compensate suggested that induction of synaptic plasticity in vitro and
for specific deficits in FMR2, which could explain the variability in memory formation in vivo are associated with increases in the
cognitive deficiencies seen in FRAXE. 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.
DENDRITIC MORPHOLOGY IN COGNITIVE DEFICITS
Changes in spine morphology are correlated with changes in
Early studies of synapse morphology in the hippocampus synaptic activity, such as occurs during induction of LTP in vitro
October 2002
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385
Review
(65). Vital to dendritic remodeling is the actin cytoskeleton (66). In The appearance of immature spines may not be due to a
the following sections, we review two diseases of human memory developmental derangement, but rather due to changes in protein
formation that also affect the morphology of dendritic spines. expression under the transcriptional control of FMRP. This theory
is supported by two lines of evidence: 1) The synaptic immaturity
FRAGILE X MENTAL RETARDATION 1 seen in FMR1 knockout mice and in human patients resembles
that which can be caused by sensory deprivation and, 2) FMR1
FMR1 is located at Xq27.3 at a unique site on the X chromosome translocates to the areas surrounding synapses following
known as the Fragile X A site (FRAXA) (67). The polymorphic stimulation of metabotropic glutamate receptors. A greater
CGG-repeat responsible for the loss of gene expression occurs at understanding of the pathogenesis of the Fragile X syndrome will
the 5' UTR of FMR1 (Figure 4). Interestingly, if the repeat number unquestionably be attained through the analysis of the function of
is between ~50 and 200, normal protein is produced and no FMRP.
dysfunction is seen. However, if the expansion exceeds 200 CGG
repeats the disease will become manifest; in some cases, more than WILLIAMS SYNDROME
1000 CGG repeats in FMR1 have been observed. The mutation of
FMR1 results in hypermethylation of the CGG expansion and of Williams Syndrome (WS) is a relatively common disorder,
the upstream CpG island in the promoter, leading to occurring once in 20,000 live births (72). WS patients exhibit an
transcriptional silencing of FMR1. The instability of the interesting idiosyncratic social behavioral syndrome they are
trinucleotide expansion during embryogenesis often leads to overly friendly. Behavioral studies of WS patients show that they
significant mosaicism in nearly 15% of patients with harboring at manifest an abnormal positive bias toward unknown individuals
least 200 CGG repeats. (73); they have been described as  never having met a stranger,
FMR1 mRNA undergoes extensive alternative splicing and can treating even people that they have just met with great familiarity.
form up to twenty alternatively sliced proteins; however, only four They also exhibit spatio-visual processing deficits, highly acute
or five protein isoforms are detectable. Almost all FMR1 protein hearing, and mild-to-severe mental retardation. WS arises from
(FMRP) consists of FMR1 isoform 7, which lacks exon 12. The deletions in chromosome 7 that typically include multiple genes.
first solid evidence suggesting a specific role for FMRP in Given the complex behavioral manifestations in WS patients,
cognition came from studies on brains of three fragile X patients Williams Syndrome provides an interesting example of genetic
that showed an increase in dendritic spine density in the CNS contributions to complex social behaviors.
(68). The dendritic spines had a long, thin morphology, which WS is associated with a 1.5 Mb deletion in chromosome
closely resembled the immature spines observed in developing 7q11.23 (74). Several genes have been identified within the WS
neurons. This suggested a role for FMR1 in neuronal maturation locus (72) including LIM Kinase 1 (LIMK-1) (75, 76). LIMK-1 is a
or development, but it was not until the investigation of a mouse target of the Rac and Rho small GTPases, and PKC signals that
model for FMR1 that putative mechanisms of FMRP action began control cytoskeletal organization (Figure 5). LIMK-1 exerts its
to emerge. effects through phosphorylating and inhibiting Actin
In 1994, a FMR1 knockout mouse was developed (69). Depolymerization Factor (ADF)/cofilin. ADF/cofilin normally
Although the animal model differs from the human cause of gene binds directly to actin and promotes its depolymerization. Thus,
disruption, absence of FMRP results in a phenotype resembling the LIMK-1 pathway is one of the specific mechanisms whereby
that in FMR1 humans. This includes macroorchidism and deficits the Rho system regulates cytoskeletal structure.
in spatial learning and associative fear-conditioned learning (70). LIMK-1 homozygous knockout mice, as expected, have
There is an overall increase in the number of dendritic spines in alterations in actin microfilaments due to derangements of actin
FMR1 mice (Figure 5). Dendritic spines of FMR1 mice are long turnover. They also manifest altered dendritic spine morphology at
and thin, mimicking the human condition. Schaffer collateral synapses in the hippocampus. Specifically, they
FMRP is a cytoplasmic RNA-binding protein that contains have fewer actin microfilaments than the normally actin-dense
three functional RNA binding motifs [two KH (heterogeneous spines, and the dendritic spines in LIMK-1 knockout mice lack the
nuclear RNA-binding protein K homology) domains and an RGG normal bulbous ending that dendritic spines exhibit. There are no
(Arg Gly Gly) box] and has been shown to associate with G apparent alterations in synaptic number or baseline synaptic
quartets present in mRNA in vivo (71). There is some evidence function, however. Like FMR2 knockout mice, LIMK-1 knockouts
that FMRP may chaperone mRNA from the nucleus to the synapse exhibit LTP that saturates at a higher level than that seen in
(Figure 5). Another possible role for FMR1 is in synaptic control mice that is, a higher maximal level of potentiation is
maturation (Figure 5). The increase of long, thin dendritic achieved with repetitive LTP-inducing stimulation. This alteration
processes and a higher density of dendritic spines observed in the in synaptic plasticity is associated with impaired learning as well.
brains of Fmr1 / mice and humans with FMR1 suggest that the Specifically, LIMK-1 knockouts show a decrease in their capacity
lack of mature synapses underlies the observed cognitive deficits. to  unlearn the location of a hidden platform in a Morris Water
386
Genes and Proteins Involved in Cognition
Maze task, once they have learned that a platform is associated from animal studies that acute inhibition of the signal in adults is
with a particular location. This is assessed using a platform sufficient to cause learning deficiencies. These types of
reversal variation of the Water Maze, where the hidden platform is considerations suggest a rethinking of our outlook on human
moved to a new location after the animal has been repeatedly learning disorders from the traditional view of them as
trained with the platform in one place. The effects on LTP and developmental problems to a new view of them as cognitive
dendritic spine morphology in the LIMK-1 knockout mouse deficiencies. This change in outlook has been precipitated by new
suggest a possible basis for the cognitive effects in WS. They also and ongoing discoveries concerning the basic signal transduction
point to the growing understanding of the importance of processes underlying learning and memory.
morphological regulation in learning and synaptic plasticity, Arguably, the holy grail quest of neuroscience research is
including, apparently, those processes occurring in the human unlocking the mystery of human cognition. Initial studies of brain
CNS. 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
CONCLUSIONS
elucidated where in the brain memories were formed and stored,
A great deal of progress has been made in the last decade in but shed little light as to the mechanisms underlying its formation.
understanding the molecular basis for deficiencies in human It was not until the molecular genetics revolution that serious
memory formation. Much of this progress has been made using progress was made in beginning to dissect the cellular and
animal models where normal gene expression has been disrupted. molecular basis of human cognition. Perhaps the most striking
Interpretation of results from knock-out animal models is difficult, observation made concerning the molecular basis of human
as one cannot rule out the possibility that expression of the altered cognitive deficiency is that no cellular process is invulnerable to
gene may not be directly involved in memory formation, but disruption. Deficits in human cognition arise from cellular defects
rather is involved in development of the relevant neural pathways. in receptor-mediated second-messenger signaling pathways
Most of the mutations we describe do not lead to gross through disruptions in chromatin structure (Figure 5). In fact, we
morphological changes in the CNS in the human or mouse. Mouse now live in a world where observations from knockout mice are
studies, where available, indicate that baseline synaptic utilized to understand the associated condition in  knockout
transmission in many of the mutations is normal as well. These humans. With all the progress that has been made understanding
observations are consistent with an ongoing need for newly cognition and the basis for deficits, the next wave of research
synthesized gene products in cognitive processing. Additionally, in should begin to shed light on how to alleviate, or possibly cure
the case of the ERK CREB CBP pathway, there is direct evidence some of these debilitating diseases.
E6-AP ubiquitin-protein ligase gene 7. Jiang, Y.H., Armstrong, D., Albrecht,
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Genes and Proteins Involved in Cognition
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]
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Volume 2, Issue 6
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