1
A Systematic Approach in Bridging
Genes to Cognitive Function
Jovan A. Nedeljkovic
Abstract— During the past two centuries, the study of memory,
learning and cognition in general has been central to three
disciplines: first philosophy, then psychology and now biology.
With emergence of high-throughput technologies for analyzing
biomolecules, and impressive accumulation of non-systemized
knowledge it is becoming possible for the first time in history to
systematically probe molecular biology basis of cognition. By
examining postsynaptic changes, biology might in recent time
revolutionize the way we perceive ourselves.
Index Terms— cognition, receptors, synapse, systems biology
cognitive function. Results of this divergence were impressive.
Biologists have accumulated mass amounts of knowledge
(data) in all these areas of research. Different brain structures
have been associated with different cognitive function, LTP
and LTD (for definitions see section III of this paper) were
related to learning, genes are being mapped to cognitive
function, etc.
In spite of all these data no unifying scheme or molecular
hypothesis was provided that would link genes to cognition.
The purpose of this paper is to propose the strategy for
systematic study of human cognitive function. We will also
show all the beauty and power of the proposed strategy by
applying it to the study of synapses.
I. HISTORICAL PERSPECTIVE
of cognitive function in humans is very old. In 19th
century, scientists started to consider how much of
cognitive function is based on heredity and how much is the
product of interactions with the environment. Galton (1865), in
his two article series [1], posed a question whether “nature or
nurture” is prevalent in cognitive function. Since then
philosophy, psychology and biology examined relationship
between genes environment and cognitive function.
Most of the work done by psychologists was “holistic” in
nature. They considered humans as the black box and
performed various experiments [2], [3] trying to comprehend
human cognition. Most of the studies revolved around
Galton’s statement. That is why adopted children and twins
were used in the studies [3]. Dominant problem in those
experiments was isolation of variables and establishing causeeffect mapping. Usually the best they could do was to say that
two variables were correlated (they change with one another).
Having all this in mind psychologists did have considerable
success in providing us with some models of human memory
[2] and learning [3], two most important cognitive functions,
but have largely failed to deal with impairments of cognitive
function, namely mental diseases.
Biologists on the other hand were more used to reductionist
thinking in solving problems. Biologists have plunged into
anatomical and physiological study of nervous system. Biology
has diverged into numerous directions trying to cope with the
problem of cognition [3]. It has studied anatomy of the brain in
hope to determine which parts of the brain are responsible for
which cognitive function. It has studied single neurons and its
networks hoping to determine where and how does the
learning occur. It has studied effects of single genes on human
S
TUDY
II. SYSTEMATIC APPROACH TO BIOLOGY OF COGNITION
We propose to use Systems Biology approach, as outlined
by [4], [5], in order to systematically approach biological
study of cognition. Our objective is the same as in the single
gene approaches. We want to link cognition all the way back
to genes. What we realize though is that we cannot go directly
from genes to phenotype (cognitive function). As stated in [4],
the main problem in predicting system level functionality
directly from genes is that most of the biological interactions
are highly non-linear. It is possible to obtain good cause-effect
relationship between certain individual genes and cognitive
function, but when we want to integrate these responses to
multiple gene cause-effect relationship we cannot simply add
them up.
Thus we suggest to systematically integrate numerous data
from previous studies in bottom-up fashion. Systematic
approach to cognitive function of humans would integrate
previous knowledge in the following manner: genome 
transcriptome  protome  organelles  synapse  cell 
circuits of cells  brain  cognition.
The task in front of us is far from easy and the goal seems
out of the reach, mostly due to a) inadequate technologies for
high throughput acquisition of data and its storage (especially
at higher levels of biological hierarchy) and to the lesser extent
due to b) inherent cellular heterogeneity in brain [6].
Nevertheless, even if the systematic understanding of higher
levels of biological hierarchy does prove to be extremely
difficult, we would gain a significant insight into biological
2
Fig 1. Model of the synapse, which can be found in most of the physiology
texts. Signaling proteins are seen to be floating in cytostol and interaction
between components are not specified. N and A represent respectively
NMDA and AMPA receptor while M is mGluR. Adapted from [12].
basis of cognition by just managing to systematically and
comprehensively probe a neuron (especially in hippocampus).
Since first four levels of integration are common to all
biological problems and thus well studied (or being studied)
[4], [5] it seems natural to start linking cognition to biology at
the synapse level. This is a good idea not only because a
synapse is next on our list of hierarchies but also since it has
been soundly hypothesized that synapses play crucial role in
learning and memory [7], [8].
III. NOTE ON SYNAPSES AND LEARNING
Learning is perhaps the single most important mechanism in
nervous system since it provides primary means of qualitative
change in the overall function of the system [9]. The modern
era on the study of the biology of learning at the cellular level
began with the discovery of long-term-potentiation (LTP) and
long-term-depression (LTD). LTP is the process whereby brief
high frequency stimulation of a neural pathway can induce
long lasting increases in the synaptic response [9]. Conversely,
LTD refers to a long lasting decrease or weakening of synaptic
strength excited by sustained, low frequency stimulation [9].
These long lasting changes in the synaptic function are
hypothesized to provide, at least in part, the cellular basis of
learning and memory [8]. Perhaps the best-studied forms of
synaptic plasticity are
N-methyl-D-asparate (NMDA) receptor-dependent LTP and
LTD. Over the years, great efforts have been placed on
studying mechanisms of synaptic plasticity. In hippocampus,
NMDA receptors have been shown to be critical for LTP.
NMDA receptors depend both on presynaptic and postsynaptic
activity [9]. Presynaptic activity is required since the NMDA
channel will not open unless excitatory neurotransmitter
glutamate (released when presynaptic neuron is active) is
bound to the receptor. Postsynaptic activity is required because
the postsynaptic membrane potential must be sufficiently
excited to cause magnesium ions (Mg+) to move out of the
opening of the NMDA receptor channel, which they would
otherwise block. Once the NMDA receptor channel opens
calcium ions (Ca++) are allowed to enter the postsynaptic
neuron. Influx of calcium ions causes a series causes a series
of not well-understood reactions resulting in the efficacy of the
primary excitatory input receptors, the AMPA (D-2-amino-3hydroxy-5-methyl-4-isoxazole-propionic acid) receptors [9]. It
has become obvious that for proper understanding of LTP
induction these postsynaptic reactions were to be deciphered.
In the last ten years considerable progress was made in
identifying proteins and enzymes involved in this postsynaptic
signaling. Some of these proteins, such as, among others, PSD95, PSD-93, and mGluR, were correlated to LTP. Consult [10]
for the full names of proteins. Function of these proteins and
their interconnectivity were mostly unknown. The best model
biology managed to produce (still found in many textbooks) is
displayed in figure 1.
IV. SYSTEMATIC DESCRIPTION OF A SYNAPSE
From previous sections it follows that synapses are indeed a
good starting point towards systematic understanding of
cognition. NMDA receptors seem to have quite an important
role in postsynaptic processing of information and learning.
Also postsynaptic receptors and proteins are probably among
the most studied objects in neurophysiology. Having all this in
mind systematic study of synapses should be started by
examining NMDA receptors.
In order to systematically study NMDA receptors Ideker’s
integrated strategy [5] for systematic study of metabolic
networks was applied. First all the genes, proteins and small
molecules involved were defined and initial model of the
molecular interactions on the basis of previous genetic and
biochemical research was established [11]. Second, biological
pathways were perturbed using some environmental, but
mainly genetic perturbations. For each perturbation,
technologies for high-throughput analysis of proteins, genes,
and their interactions (such as mass spectrometry, highefficiency protein separation, 2D gel electrophosesis) [11]
were used to obtain the quantitative measure of the state of the
system. Third, this data was integrated with the existing model.
Fourth, new hypothesis was made and the above steps were
used to test the model. After numerous iterations the model
displayed on figure 2 was obtained.
What is immediately obvious by looking at the model is
that many of the downstream signaling molecules involved in
NMDA receptor signaling are actually physically coupled to it
through variety of protein-protein interactions [11]. This is
contrary to the previous model (more precisely belief) that
these molecules are separate components floating in cytosol.
Careful analysis of this model and data reveal a lot of
interesting results about synapse and its plasticity:
1.
NMDA receptor is in the same physical complex with
mGluR (previously shown on figure 1 as separate),
PSD-95, GKAP, Shank, and Homer [12].
3
Fig 3. Network connectivity of NMDA receptor complex proteins. The circle
indicates the location of NMDA receptor subunits. Individual proteins are
represented once. Adapted from [14].
Fig 2. Assembly of proteins found in the NMDA receptor complex.
Molecules found in the systematic analysis of the complex are depicted as
well as the interactions between them. Adapted from [11].
2.
Postsynaptic
D-2-amino-3-hydroxy-5-methyl-4isoxazole-propionic acid (AMPA) receptors, which
mediate fast synaptic transmission and are thought to
comprise the expression of LTP, are found to be
distinct to the regulatory complex between
NMDA
receptor and mGluRs [12]
3.
Modular organization became apperant. Proteins of
similar function are grouped together [12]. A-Kinase
Anchoring protein (AKAP) plays crucial role in
signaling between modules [12].
4.
There exist multiple signaling pathways between
proteins. The characterization of these multiple
signaling pathways in NMDA receptor complex
provides a model in which signaling complex (by
directing signals to different output pathways) can
orchestrate the ensemble of changes that reflect neural
plasticity (such as AMPA receptor phoshorylation,
trafficking,
cytoskeletal
changes,
translation
activation, etc.) [12].
5.
Perhaps the most surprising aspect of this analysis was
the diversity and number of signal transduction
proteins found in these complexes. Protomic studies
indicate a high degree of complexity with 185 proteins
in these complexes [13]. Fifty-one of these proteins
were identified to be involved with synaptic plasticity
(i.e. LTP and LTD), 46 of them were related to major
psychiatric disorders and 39 of them to behavior [13].
This result confirms belief that synapses are related to
cognitive function.
Further insights in the functioning of synapse can be
obtained by studying the overall structure of NMDA receptor
complex and its topology. We can represent molecule
connectivity in the NMDA receptor complex in the form of a
graph or a network [14] (see figure 3).
At first look this graph looks confusing and it is hard to
imagine it can help. Everything looks connected to everything
else. However we can use knowledge of networks that was
developed in non-biological (more precisely mathematical)
settings [15] in order to deduce something from this
representation.
The analyses of this graph reveal that proteins in NMDA
complex are connected in the network that includes occasional
long-range connections and a small number of highly
connected nodes (called hubs), which is know in mathematics
as a free-scale network [15] (see fig4). Furthermore it has been
documented [15] that this architecture is characteristic of all
metabolic networks in eukaryotes, implying that principle of
underlying protein interactions was evolutionary conserved.
The most dominant feature (in characterizing the properties)
of scale-free networks is their small world property (see fig.4)
[14]. Though these networks span a huge number of proteins
(in biological systems) each two of them are connected
through a small number of mediators. This property is
quantified using network diameter (average of the shortest path
between all pairs of nodes in a network) [14]. NMDA receptor
complex exhibited the diameter of 3.26, meaning that in
general only two mediators separate any two proteins in the
complex.
This implies that NMDA complex is highly interconnected
structure, which suggests that changes in one protein could
easily change the function of many other proteins. This tight
interconnection of proteins also indicates a number of multiple
paths between them, providing the whole complex with the
Fig 4. a) A scale-free network has a few nodes with higher numbers of
connections (hubs, indicated with darker nodes). b) Probability that any given
4
node in the scale-free network has k connections follows the power law.
Adapted from [6].
remarkable robustness with respect to its overall function [14].
The above two sentences may seem contradictory to one
another but Grant [14] uses a simple analogy to the automobile
to demonstrate that these statements can cohabit. In the car
analogy the loss of any component of the car can affect the
system, but most of the pieces are accessories with little role to
the overall function. These properties might provide more
evidence why single gene approach to cognitive function was
not very successful.
In addition to the above methodologies Grant et al, [14]
have systematically knocked out node by node (i.e. molecule
by molecule) from NMDA complex and observed the network
diameter and overall function. In this way they have tested the
biological significance of network topology on synaptic
plasticity and cognitive function. Results were not surprising.
Hub nodes proved to be essential for a function of the network.
V. CONCLUSIONS AND FUTURE WORK
As demonstrated in a previous section the results of
applying system biology methodologies to the study of NMDA
complex, and synapse in general, are outstanding. A
comprehensive model of postsynaptic signaling complex was
obtained. This model was more realistic and in agreement with
experimental data, unlike model introduced in section II of this
paper.
Here instead of iterating what was already said, we would
like to stress out a potentially huge benefit of this systematic
approach to cognition, which was just briefly touched in
previous section. Systematic study of NMDA receptor
complex identified 185 proteins [13] in this complex and most
importantly grouped them into those that affect synaptic
plasticity. (51 of them), those that are related to major
psychiatric disorder (46 of them) and those that are involved
with behavior (39 proteins). These results strongly suggest that
these complexes and more generally synapses are not
exclusively related to LTP and LTD, but as well as with
behavior and major psychiatric disorders. Physiology and
biology with all their sub disciplines have had a very limited
success in dealing with neuropathologies and major psychiatric
disorders. Pharmacology has tried so far to deal with these
issues by targeting single molecules in our body. It is by now
obvious that this approach has serious limitations. With our
systematic knowledge of these protein complexes we can
choose single molecule targets in a smarter manner (possibly
concentrate on network hubs) or target group of molecules that
are indicated in the network to have strong influence on a
particular function. If we were able to target proper groups of
molecules it would be a major scientific breakthrough.
Hence by applying systematic approach towards
understanding of synapse we gained multiple insights from
different perspectives on the function of the synapse. Though
the results in the above discussion are quite remarkable this is
just the first step towards linking molecular biology to
cognitive function. There is yet a lot of work to be done on
both synaptic level of organization as well as on higher levels
of hierarchy.
On the level of NMDA receptor complex we can try to
incorporate all the new molecules, primarily enzymes (that are
now showing up in the postsynaptic signaling complex), into
our growing NMDA signaling model. Major challenge though
is trying to understand nonlinear dynamics that are prevalent
in these complexes. This is job for mathematicians and some
work is already being done [16].
On the level of synapses other receptors should be studied in
similar systematic manner. Till recently little work has been
done on systematic understanding of higher levels of
hierarchy. Recently a group of world-renowned scientists have
been formed with the idea to study brain molecular anatomy.
They are trying to make an all-inclusive mapping of mainly
genes and proteins to different types of cells in the brain [17].
Perspectives are enormous, technologies limited but we
hope that this paper has demonstrated superiority of systematic
approach in integrating biological information from gene to
cognition. This process has come about as an evolution of
different approaches to the study of cognition and biology, but
it for sure has a potential to, in our life span, revolutionize
cognitive science, and ultimately the way we perceive
ourselves.
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