Aspartate and glutamate act as neurotransmitters in the brain by facilitating the transmission of information from neuron to neuron. Too much aspartate or glutamate in the brain kills certain neurons by allowing the influx of too much calcium into the cells. This influx triggers excessive amounts of free radicals, which kill the cells. The neural cell damage that can be caused by excessive aspartate and glutamate is why they are referred to as “excitotoxins.” They “excite” or stimulate the neural cells to death. Read More.
A new study begins to clarify how brain structure and chemistry give
rise to specific aspects of “fluid intelligence,” the ability to adapt
to new situations and solve problems one has never encountered before.
The study, reported in the journal NeuroImage, links higher
concentrations of a marker of energy production in the brain with an
improved ability to solve verbal and spatial problems. It also finds an
association between brain size and number-related problem-solving.
The analysis involved 211 research subjects, making it the largest
study to date linking brain chemistry and intelligence in living humans,
said University of Illinois postdoctoral researcher Erick Paul, who led the work with research scientist Ryan Larsen and Illinois neuroscience professor Aron Barbey. The work was conducted in the Decision Neuroscience Laboratory at the Beckman Institute for Advanced Science and Technology. More studies will be needed to confirm and extend the findings, the researchers said.
“In our data, we observed two facets of fluid intelligence – one that
involves quantitative or numeric reasoning, and another that involves
verbal or spatial reasoning,” Paul said. “A similar separation of
reasoning abilities has been demonstrated in previous studies.”
The researchers conducted magnetic resonance spectroscopy to analyze
brain concentrations of a compound called NAA (N-acetyl aspartate), a
byproduct of glucose metabolism and a marker of energy production. They
measured brain volume in all subjects using magnetic resonance imaging.
“We found that the quantitative reasoning component of intelligence
correlated with brain volume, but not with the concentration of NAA in
the brain,” Paul said. “And the verbal and spatial components of
intelligence correlated with NAA, but not with brain volume.”
The team observed the same basic relationships when analyzing males and females separately.
The findings add to the evidence that fluid intelligence involves distinct yet interrelated processes in the brain, Paul said.
“Surely there are many things about the brain that determine a
person’s intelligence, and the goal is to try to tease apart that
puzzle,” he said. “These two brain biomarkers, brain volume and NAA, are
each giving us independent information about fluid intelligence. There
are different properties of the brain that we can measure, and these
different properties go with these different facets of fluid
“Our findings contribute to a growing body of evidence to suggest
that intelligence reflects multiple levels of organization in the brain –
spanning neuroanatomy, for example brain size, and neurophysiology,
such as brain metabolism – and that specific properties of the brain
provide a powerful lens to investigate and understand the nature of
specific intellectual abilities,” Barbey said.
Day 5: Insulin.
I need insulin to survive, so why not get it tattooed on my leg?? This is the hexamer structure of insulin aspart in 2D (also known as artificial insulin). I absolutely love this tattoo!
Antibodies defend the body against bacterial, viral, and other invaders. But
sometimes the body makes antibodies that attack healthy cells. In these
cases, autoimmune disorders develop.
Immune abnormalities in patients with psychosis have been recognized
for over a century, but it has been only relatively recently that
scientists have identified specific immune mechanisms that seem to
directly produce symptoms of psychosis, including hallucinations and
This ‘immune hypothesis’ is supported by new work published by
Pathmanandavel and colleagues in the current issue of Biological
Psychiatry. They detected antibodies to the dopamine D2 receptor or the
N-methyl-D-aspartate (NMDA) glutamate receptor in a subgroup of children
experiencing their first episode of psychosis, but no such antibodies
in healthy children. Both are key neural signaling proteins that have
previously been implicated in psychosis.
“The antibodies we have detected in children having a first episode
of acute psychosis suggest there is a distinct subgroup for whom
autoimmunity plays a role in their illness,” said Dr. Fabienne Brilot,
senior author on the article and Head of the Neuroimmunology Group at
The Children’s Hospital at Westmead in Sydney.
Karrnan Pathmanandavel, Jean Starling, Vera Merheb, Sudarshini Ramanathan, Nese Sinmaz, Russell C. Dale, Fabienne Brilot. Antibodies to Surface Dopamine-2 Receptor and N-Methyl-D-Aspartate Receptor in the First Episode of Acute Psychosis in Children. Biological Psychiatry, 2015; 77 (6): 537 DOI: 10.1016/j.biopsych.2014.07.014
Antibodies to Brain Proteins May Trigger Psychosis
Antibodies defend the body against bacterial, viral, and other invaders. But sometimes the body makes antibodies that attack healthy cells. In these cases, autoimmune disorders develop.
Immune abnormalities in
patients with psychosis have been recognized for over a century, but it has
been only relatively recently that scientists have identified specific immune
mechanisms that seem to directly produce symptoms of psychosis, including
hallucinations and delusions.
This ‘immune hypothesis’ is
supported by new work published by Pathmanandavel and colleagues in the current
issue of Biological Psychiatry. They
detected antibodies to the dopamine D2 receptor or the N-methyl-D-aspartate (NMDA) glutamate receptor in a subgroup of children
experiencing their first episode of psychosis, but no such antibodies in
healthy children. Both are key neural signaling proteins that have previously
been implicated in psychosis.
“The antibodies we have
detected in children having a first episode of acute psychosis suggest there is
a distinct subgroup for whom autoimmunity plays a role in their illness,” said
Dr. Fabienne Brilot, senior author on the article and Head of the
Neuroimmunology Group at The Children’s Hospital at Westmead in Sydney.
It almost seems like a dirty
trick. For decades psychiatrists have administered drugs that stimulate
dopamine D2 receptors or block NMDA receptors. These drugs may briefly produce side
effects that resemble symptoms of psychotic disorders, including changes in
perception, delusions, and disorganization of thought processes. The current
findings suggest that people may develop antibodies that affect the brain in
ways that are similar to these psychosis-producing drugs.
“This study adds fuel to the
growing discussions about the importance of antibodies targeting neural
proteins and it raises many important questions for the field. Do these
antibodies simply function like drugs in the brain or do they ‘attack’ and
damage nerve cells in some ways?” questioned Dr. John Krystal, Editor of Biological Psychiatry. “Also, are these
antibodies producing symptoms in everyone or do they function as a probe of an
underlying, perhaps genetic, vulnerability for psychosis?”
Importantly, work is
advancing rapidly in this area. Less than a decade ago, anti-NMDA receptor
encephalitis was first identified, a disease characterized by inflammation of
the brain that causes acute psychiatric symptoms including psychosis. It is
commonly misdiagnosed as schizophrenia or bipolar disorder, but is a form of
treatable brain inflammation caused by antibodies that attack the brain’s NMDA
“The data from this study
suggests that better interventions are possible, providing hope that major
disability can be prevented for the subset of children experiencing acute
psychosis with antibodies,” Brilot added. “These findings also contribute
significantly to an emerging acceptance in the field of the involvement of
autoimmune antibodies in neurological diseases. Combined, these investigations
are providing a better understanding of the biology of psychiatric and
neurological diseases, as well as pointing to novel treatment approaches for
children with these debilitating illnesses.”
Structural biologists at Cold Spring Harbor Laboratory (CSHL) and
Janelia Research Campus/HHMI, have obtained snapshots of the activation
of an important type of brain-cell receptor. Dysfunction of the receptor
has been implicated in a range of neurological illnesses, including
Alzheimer’s disease, Parkinson’s disease, depression, seizure,
schizophrenia, autism, and injuries related to stroke.
CSHL Associate Professor Hiro Furukawa, the research team has obtained
images of the NMDA (N-methyl, D-aspartate) receptor in active,
non-active, and inhibited states. Understanding how NMDA receptors
activate is critical in designing novel therapeutic compounds. NMDA
receptors are embedded in the membrane of many nerve cells in the brain
and are involved in signaling between cells that is essential to basic
brain functions, including learning and memory formation.
Structurally, the NMDA receptor is made up of various protein segments,
called domains, which together resemble a hot air balloon. The upper,
balloon-like portion is comprised of the amino terminal domain (ATD);
protruding from the outer surface of the cell is the ligand binding
domain (LBD); and the lower, basket-like portion of the receptor, called
the transmembrane domain (TMD), drops down inside the cell.
of the NMDA receptor requires binding of brain chemicals called
neurotransmitters at specific sites on the LBD. This binding together
with structural rearrangement of the ATD triggers the opening of the
channel formed by the TMD. This molecular event causes charged atoms
called ions flow into the cell. When this occurs in many channels at
once, an electrical current is generated that rapidly propagates through
the neuron and triggers the release of neurotransmitters. These
chemical signals, in turn, bind to receptors on neighboring cells.
accumulating knowledge regarding the structure of the NMDA receptor and
its various components, precise, details about the structural movements
leading to the process of opening of the ion channel have not been
described previously and the mechanism of receptor activation has
In addition to describing the NMDA receptor’s
balloon-like structure, Furukawa and the team of CSHL structural
biologists have previously revealed many important features of NMDA
receptors, including the distinctive ways in which a number of drug
compounds attach to the receptor at its various binding sites. “The NMDA
receptor architecture itself is quite complicated,” says Furukawa, “but
most recently we’ve been really fascinated by how each of its domains
moves in a sophisticated but organized manner.”
To learn more about the dynamics of NMDA receptor activation, the
researchers combined two molecular imaging techniques, x-ray
crystallography and single-particle electron cryomicroscopy, and
observed structures of the NMDA receptor in three specific
configurations, the activated, non-active, and inhibited states.
of these configurations was achieved by the binding of different
molecules to the receptor. For example, the activated state required the
binding of the neurotransmitters glycine and glutamate, while the
binding of the compound ifenprodil resulted in the inhibited state that
forces the channel to be closed. The researchers used these molecular
structures, published in Nature, to infer how the receptor’s
various subdomains rearrange themselves when transitioning from a
non-active to the active state.
“With the technology available
today, we don’t see continuous movement but instead we see snapshots of
NMDA receptors in different functional states,” Furukawa notes.
Superimposing the crystal structure of the NMDA receptor in each of the
three functional states revealed which components move—typically by
rotating slightly relative to one another—when the ion channel opens.
The researchers observed that activation required opening of the
bi-lobed architecture of the one of the two ATD subdomains and a
reorientation of the ATD as a whole. These changes lead to additional
rotations at various points throughout both the ATD and LBD, causing the
ion channel pore to open, similar to the opening of a camera shutter.
says that studying how components of the NMDA receptor move during
activation and inactivation can help scientists create computer
simulations to predict how the structures of various drug molecules
might impact these movements. “Unless we have a library of molecular
structures, people in the field won’t be able to run those simulations,”
says Furukawa. “We hope that this new finding will help pharmacologists
come up with better therapeutic compounds that have minimal side
Immuno-Psychiatry: When Your Body Makes Its Own Angel Dust
A new study in Biological Psychiatry reports structural
brain damage from an autoimmune encephalitis that impairs behavior in
ways that are somewhat similar to the effects of “angel dust”.
body sometimes makes substances that have effects on the brain in ways
that resemble the effects of illicit drugs. In their paper, the authors
report findings on a syndrome called anti-NMDA receptor encephalitis
that arises when the body makes antibodies that target one of the
subunits of the N-methyl-D-aspartate (NMDA) subtype of receptor for the chemical messenger, glutamate.
antibodies appear to mimic effects produced by the drug phencyclidine
(PCP), also known as “angel dust”, which produces a schizophrenia-like
syndrome by blocking the NMDA glutamate receptor. Schizophrenia itself
is also associated with NMDA receptor dysfunction.
of the study, Dr. Carsten Finke, Professor at
Charité–Universitätsmedizin Berlin, explains, “Anti-NMDA receptor
encephalitis is a recently discovered autoimmune disorder of the brain,
which causes a severe neuropsychiatric syndrome with behavioral changes,
psychosis, memory loss, and decreased levels of consciousness. Although
many patients recover well, the majority suffer from long-term
In this issue of Biological Psychiatry,
Finke and his colleagues analyzed multimodal magnetic resonance imaging
data from 40 patients who were recovering from anti-NMDA receptor
They discovered that the patients had structural
damage of the hippocampus and impaired hippocampal microstructural
integrity, which strongly correlated with memory performance, disease
severity, and disease duration. The hippocampus is a brain structure
that plays an important role in memory.
“The results of the study
therefore reveal a structural correlate of the persisting memory
deficits - the chief complaint affecting daily life of patients after
the acute disease stage,” said Finke. “Furthermore, these observations
are also in line with evidence that dysfunction of hippocampal NMDA
receptors causes severe amnesia.”
These findings suggest that the
disease, which can be particularly difficult to quickly diagnose, is
critical to treat promptly because the behavioral symptoms can be signs
that the antibodies are actively damaging the brain.
psychosis syndromes arising from the development of anti-NMDA receptor
antibodies are extremely important to diagnosis and treat,” commented
Dr. John Krystal, Editor of Biological Psychiatry. “They may be
easily misdiagnosed as the psychiatric disorders that they
superficially resemble. Nonetheless, these syndromes highlight the
importance of NMDA receptor signaling for the genesis of symptoms
associated with psychotic disorders.”
The realization hit him like a ton of bricks. The moment he thought of it, he deemed himself crazy. He wasn’t. The scream was coming from the stone itself. He reached out to place his palms on the surface of the pillar.
aka. the Outlander AU where Fitz is a WWII veteran and Jemma is a healer for the clan Mackenzie
Biologists at Cold Spring Harbor Laboratory (CSHL) report today that they have succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses, including Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke.
The team’s atomic-level picture of the intact NMDA (N-methyl, D-aspartate) receptor should serve as template and guide for the design of therapeutic compounds.
The NMDA receptor is a massive multi-subunit complex that integrates both chemical and electrical signals in the brain to allow neurons to communicate with one another. These conversations form the basis of memory, learning, and thought, and critically mediate brain development. The receptor’s function is tightly regulated: both increased and decreased NMDA activities are associated with neurological diseases.
Despite the importance of NMDA receptor function, scientists have struggled to understand how it is controlled. In work published today in Science, CSHL Associate Professor Hiro Furukawa and Erkan Karakas, Ph.D., a postdoctoral investigator, use a type of molecular photography known as X-ray crystallography to determine the structure of the intact receptor. Their work identifies numerous interactions between the four subunits of the receptor and offers new insight into how the complex is regulated.
“Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough,” says Furukawa. “To understand how this complex functions you need to see it all together, fully assembled.”
For such a large complex, this was a challenging task. Using an exhaustive array of protein purification methods, Furukawa and Karakas were able to isolate the intact receptor. Their crystal structure reveals that the receptor looks much like a hot air balloon. “The ‘basket’ is what we call the transmembrane domain. It forms an ion channel that allows electrical signals to propagate through the neuron,” explains Furukawa.
An ion channel is like a gate in the neuronal membrane. Ions, small electrically charged atoms, are unable to pass through the cell membrane. When the ion channel “gate” is closed, ions congregate outside the cell, creating an electrical potential across the cell membrane.
When the ion channel “gate” opens, ions flow in and out of the cell through the channel pores. This generates an electrical current that sums up to create pulses that rapidly propagate through the neuron. But the current can’t jump from one neuron to the next. Rather, the electrical pulse triggers the release of chemical messengers, called neurotransmitters. These molecules traverse the distance between the neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells. There, they act much like a key, unlocking ion channels within the receptor and propelling the electrical signal across another neuron and, ultimately, across the brain.
The “balloon” portion of the receptor that Furukawa describes is found outside the cell. This is the region that binds to neurotransmitters. The structure of the assembled multi-subunit receptor complex, including the elusive ion channel, helps to explain some of the existing data about how NMDA receptors function. “We are able to see how one domain on the exterior side of the receptor directly regulates the ion channel within the membrane,” says Furukawa. “Our structure shows why this particular domain, called the amino terminal domain, is important for the activity of the NMDA receptor, but not for other related receptors.”
This information will be critical as scientists work to develop drugs that control the NMDA receptor. “Our structure defines the interfaces where multiple subunits and domains contact one another,” says Furukawa. “In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”
Interviewer; David, you've referred to you once as part of the MTV generation - what specifically does that mean?
David Garrett; I grew up in a time with many vices, Consumerism, Internet, TV, etc. That belongs to everything these days. That's why I know what young people respond. Of course, I'm grown up with the tradition of classical music,but today it makes me just as much fun, a bit exhaust the possibilities, and not just to play purely classical.
The N3A receptor, as modeled here by the UB researchers, may be silent
under normal conditions, but can be reactivated through the unique site
(in red) under acidic conditions, such as after a stroke or seizure)
Strokes, seizures, traumatic brain injury
and schizophrenia: these conditions can cause persistent,
widespread acidity around neurons in the brain. But exactly how
that acidity affects brain function isn’t well
In a paper published in March in Scientific Reports, University
at Buffalo researchers have begun to unravel some of the puzzle.
They found that an elusive brain receptor may play an important
role in the death of neurons from neurological diseases.
The UB researchers study a family of brain receptors that are
critical to learning and memory, called NMDA (N-methyl-D-aspartate)
receptors. They found that one of these receptors called N3A
functions through a different mechanism than all other NMDA
“We found that in contrast to all other NMDA receptors,
acidity can reactivate dormant N3A receptors,” said Gabriela
K. Popescu, PhD, senior author and professor in the Department of
Biochemistry in the Jacobs School of Medicine and Biomedical
Sciences at UB. “This insight led us to hypothesize that N3A
receptors are silent in normal conditions, which may explain why
other researchers have failed to observe them
Popescu and Kirstie A. Cummings, lead author and doctoral
candidate in the UB Department of Biochemistry, found that when the
N3A receptors were exposed to acidic conditions, as occurs in brain
disorders such as stroke or epilepsy, they reactivate, causing
neurons to become more sensitive to the neurotransmitter glutamate,
which can, under certain circumstances, kill them.
The research was done in cell culture with recombinant
“Given that acidity increases after a stroke or an
epileptic seizure, reactivation of N3A receptors may be one reason
why neurons die after these neurologic events,” said Popescu.
“So finding ways to prevent acidification or the reactivation
of N3A receptors may prevent brain damage from strokes or seizures,
She added that N3A proteins appear to be more abundant in brains
of people with schizophrenia. “This is in line with our
findings, since schizophrenia, a disease associated with high
acidity in the brain, causes brains to shrink,” she said.
Popescu noted that the finding also sheds much needed light on
the N3A receptors. “Since their discovery more than 20 years
ago, attempts to understand the roles of N3A receptors in the brain
have been unsuccessful,” she said. “Because many labs
have failed to record N3A activity from neurons, some researchers
even began to doubt their relevance to brain activity.”
The new paper reveals that electrical currents passed by N3A
receptors can excite cells in response to acidity, which makes them
different from all other NMDA receptors.
The researchers have identified the site on the receptor where
acidity acts to reactivate these receptors, a different location
from the site where acidity acts to inhibit all other NMDA
“This site is new and unique and thus can be used to make
drugs that are very specific to the N3A receptor,” said
Alzheimer’s disease drug-development pipeline: few candidates, frequent failures
Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.
We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.
During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).
The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.