NMDA Receptors
NMDA Receptors
Glutamate is the most widespread neurotransmitter in the human brain, being present in over 90%
of synaptic clefts. Therefore, in 2019, we started our research from the hypothesis that its receptors
might play a very important role in fluid intelligence.
[Link]
NMDA Receptors
• One of the main receptors that glutamate activates is the NMDA receptor.
• NMDA receptors are composed of subunits: NR1, NR2A, NR2B, etc.
• Each NMDA receptor is made up of 4 subunits, two of which will always be of the NR1/GLUN1
type (synonyms), while for the other two positions, there are numerous possible combinations
(NR2A & NR2B, NR2B & NR2B, NR3A & NR2C, etc.). These combinations will determine the
duration for which the receptor's ion channel remains open.
NMDA Receptors
The ratio between the expression of NR2B
and NR2A subunits has, as you will see, a
significant impact on cognitive abilities in
most mammals.
The higher the NR2Bratio (cortical neurons)
= the higher the cognitive function.
two NR2A subunits / NMDA receptor – the
ion channel remains open for approximately
25 ms.
two NR2B subunits / NMDA receptor – the
ion channel remains open for approximately
100 ms.
The study we present to you now
was conducted and published in
2018, with the aim of analyzing
how two species of birds (wild
finches) considered "close
relatives" solve a set of problems.
Loxigilla barbadensis – High
NR2B:NR2A Ratio/Supraunitary
Tiaris bicolor – Low NR2B:NR2A
Ratio/subunitary
L. barbadensis vs T. bicolor
GRIN2B gene - NR2B subunit
Unsurprisingly, individuals
of the L. barbadensis
species performed much
better on most tasks than
those of the T. bicolor
species.
Daca va uitati la figura
alaturata se poate vedea
media numarului de
incercari necesare pentru
finalizarea unui task pentru
fiecare dintre cele doua
specii.
Ratie NR2B:NR2A ridicata
Ratie NR2B:NR2A scazuta
Articol complet: [Link]
Where is the GRIN2B gene
expressed the most?
A brief parenthesis
Analysis of Synaptic Gene Expression in the
Neocortex of Primates Reveals Evolutionary
Changes in Glutamatergic Neurotransmission
Another noteworthy point about the expression level of the NR2B subunit is that, among
all primates, our species has the highest level.
Articol complet: [Link]
Delay cell firing, working memory, NR2B
(THE HOLY GRAIL OF WORKING MEMORY)
Study 1
Study 1
Forebrain NR2B Overexpression Facilitating the Prefrontal
Cortex Long-Term Potentiation and Enhancing Working
Memory Function in Mice
Articol complet: [Link]
Study 1
NR2B EXPRESSION
Control vs
Transgenic
Working Memory
Study 2
Study 2
Neural substrates of working memory in the
prefrontal cortex
Articol complet: [Link]
Study 3
Study 3
NMDA Receptors
Subserve Persistent
Neuronal Firing during
Working Memory in
Dorsolateral Prefrontal
Cortex
Full Article:
[Link]
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%[Link]%2Fretrieve%2Fpii
%2FS089662731300038X%3Fshowall%3Dtrue
Study 3
Study 3
Study 3
Ro25-6981 – selective NR2B antagonist
Study 3 Ro25-6981 – selective NR2B antagonist
Study 3
Study 4
Study 4
NR2B subunit in the prefrontal cortex: A double-edged sword for
working memory function and psychiatric disorders
Abstract
The prefrontal cortex (PFC) is a brain region featured with working memory function. The exact mechanism of how
working memory operates within the PFC circuitry is unknown, but persistent neuronal firing recorded from
prefrontal neurons during a working memory task is proposed to be the neural correlate of this mnemonic encoding.
The PFC appears to be specialized for sustaining persistent firing, with N-methyl-D-aspartate (NMDA) receptors,
especially slow-decay NR2B subunits, playing an essential role in the maintenance of sustained activity and normal
working memory function.
However, the NR2B subunit serves as a double-edged sword for PFC function. Because of its slow kinetics, NR2B
endows the PFC with not only “neural psychic” properties, but also susceptibilities for neuroexcitotoxicity and
psychiatric disorders. This review aims to clarify the interplay among working memory, the PFC, and NMDA
receptors; demonstrate the importance of the NR2B subunit in the maintenance of persistent activity; understand
the risks and vulnerabilities of how NR2B is related to the development of neuropsychiatric disorders; identify gaps
that currently exist in our understanding of these processes; and provide insights regarding future directions that
may clarify these issues. We conclude that the PFC is a specialized brain region with distinct delayed maturation,
unique neuronal circuitry, and characteristic NMDA receptor function.
The unique properties and development of NMDA receptors, especially enrichment of NR2B subunits, endows the
PFC with not only the capability to generate sustained activity for working memory, but also serves as a major
Full article:
vulnerability to environmental [Link]
insults and risk factors for psychiatric disorders.
Study 4 “At the favorable NR2B/2A ratio, the adult PFC is
NR2B subunit in the prefrontal cortex: A capable of optimal working memory performance,
double-edged sword for working memory which sets the stage for more complex prefrontal-
function and psychiatric disorders dependent cognition, such as cognitive and
behavioral flexibility, as well as attention.
In contrast, deviation from this optimal ratio
results in alterations to working memory and
prefrontal-dependent cognition. A reduced
NR2B/NR2A ratio induced by either decreased
expression levels of NR2B or increased levels of
NR2A will result in lower than normal cognitive
performance in all facets due to limited synaptic
plasticity and Ca2+-dependent signaling, including
impaired working memory, cognitive and
behavioral inflexibility, and diminished learning
and memory capability.
On the other hand, a high NR2B/NR2A ratio
induced by either increased NR2B or decreased
NR2A will improve working memory and
cognitive performance, yet exposes the brain to
hyperexcitability, neuropathic pain, and excitotoxic
vulnerability.”
NR2B & IQ – human studies
Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on
Study 1 prefrontal function during working memory performance
Study 1
Study 1 Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on
prefrontal function during working memory performance
There is even a condition where the GRIN2B gene is nonfunctional, and
unfortunately, this results in severe intellectual and motor disabilities.
• [Link]
Study 2
Study 2
Identification of a genetic cluster influencing
memory performance and hippocampal
activity in humans
Articol complet: [Link]
Study 3
Study 3
Variation in GRIN2B
Contributes to
Weak Performance
in Verbal Short-
Term Memory in
Children With
Dyslexia
Articol complet: [Link]
Study 4
Study 4
GRIN2B mediates susceptibility to
intelligence quotient and cognitive
impairments in developmental dyslexia
Articol complet: [Link]
Study 4
Study 4
Study 4
Study 5
Study 5
GRIN2B predicts attention problems among
disadvantaged children
Study 5
Articol complet: [Link]
Study 5
CBLC = Child Behavior Checklist
Articol complet: [Link]
Study 6
Functional human GRIN2B promoter polymorphism and variation of
mental processing speed in older adults
Discussion
What is the reason for which an increased NR2B ratio has such a pronounced pro-cognitive effect?
The main difference between an individual with a high IQ and one with a normal or even low IQ is the time in
which information is processed in the brain. The higher the fluid intelligence, the longer the information is
processed, and this significantly influences the "resolution" of mental representations.
As mentioned in the initial slides of the chapter on NMDA receptors, if the ionic channel of the receptor has an
NR1-NR1-NR2A-NR2A composition, it remains open for approximately 25 ms. However, if the composition is
NR1-NR1-NR2B-NR2B, the time the ionic channel remains open increases to 100 ms.
Obviously, when we intervene and change the expression level of the NR2B subunit, all we are doing is
increasing the processing time of information in the brain, which will facilitate connectivity (areas/modules that
do not interact frequently with each other start to do so) and implicitly the ability to understand.
How does siP work?
siP (small interfering peptide) will occupy the phosphate group
site on serine 1116 of the NR2B subunit and, implicitly, will
decouple it from CDK5.
Small interfering peptide's effect on
neurotransmission
Given the importance of NR2B in
mediating the potentiation of
synaptic transmission during
plasticity, we assessed the effects of
NR2B siP on extracellularly
recorded field excitatory
postsynaptic potentials (fEPSP) in
the hippocampal CA3-CA1 pathway.
Treatment of hippocampal slices
with NR2B siP rapidly induced a
1.9-fold increase in fEPSP slope
compared to slices infused with a
control peptide (Figure 5D and E).
Upon washout of the NR2B siP,
fEPSP slopes progressively
decreased until they reached steady-
state levels with fEPSP slopes that
were 1.6-fold greater than control
treated slices.
siP vs cdk5 knockout
If we look at the accompanying figure, we notice one thing,
namely that "general inhibition“(gene knockout) of cdk5 is not
the same as the selective inhibition of the interaction between
cdk5 and nr2b at ser1116. Why? Because cdk5 has many other
functions.
This does not mean that general inhibition will not have pro-
cognitive effects, but they will by no means be as pronounced
as in the case of selective inhibition.
(E) – SIP
VS
(G) – CdK5 cKO
