ScienceDaily (Jan. 15, 2010) — Our energy-hungry brains operate reliably and efficiently while processing a flood of sensory information, thanks to a sort of neuronal thermostat that regulates activity in the visual cortex, Yale researchers have found.
actions of inhibitory neurons allow the brain to save energy by suppressing non-essential visual stimuli and processing only key information, according to research published in the January 13 issue of the journal Neuron.
"It's called the iceberg phenomenon, where only the tip is sharply defined yet we are aware that there is a much larger portion underwater that we can not see," said David McCormick, the Dorys McConnell Duberg Professor of Neurobiology at Yale School of Medicine, researcher of the Kavli Institute of Neuroscience and co-senior author of the study. "These inhibitory neurons set the water level and control how much of the iceberg we see. We don't need to see the entire iceberg to know that it is there."
The brain uses the highest percentage of the body's energy, so scientists have long wondered how it can operate both efficiently and reliably when processing a deluge of sensory information. Most studies of vision have concentrated on activity of excitatory neurons that fire when presented with simple stimuli, such as bright or dark bars. The Yale team wanted to measure what happens outside of the classical field of vision when the brain has to deal with more complex scenes in real life.
By studying brains of animals watching movies of natural scenes, the Yale team found that inhibitory cells in the visual cortex control how the excitatory cells interact with each other.
"We found that these inhibitory cells take a lead role in making the visual cortex operate in a sparse and reliable manner," McCormick said.
James Mazer was co-senior author of the paper with McCormick. Bilal Haider, a Yale graduate student, was lead author. Other Yale authors of the paper were Matthew R. Krause, Alvaro Duque, Yuguo Yu and Jonathan Touryan.
The work was funded by the National Eye Institute and the Kavli Foundation.
Friday, January 15, 2010
Monday, December 14, 2009
Don't I Know You? How Cues and Context Kick-Start Memory Recall
ScienceDaily (Dec. 12, 2009) — We have all had the embarrassing experience of seeing an acquaintance in an unfamiliar setting. We know we know them but can't recall who they are. But with the correct cues from conversation or context, something seems to click and we can readily access very rich and vivid memories about the individual.
A team of researchers from the University of Toronto and the Krembil Neuroscience Centre at the University Health Network have shed some light on this mysterious process, discovering that the hippocampus, a brain region in the temporal lobe, is only involved when cues enable us to recall these rich memories.
"We used a technique called functional Magnetic Resonance Imaging (fMRI) that allows us to identify brain regions engaged during specific types of mental processes," says Melanie Cohn, a postdoctoral fellow in neuropsychology and lead author of the paper published online December 8 by the Proceedings of the National Academy of Sciences.
In the first stage of the study, healthy young adults were exposed to pairings of oddly unrelated words, such as "alligator" and "chair," and invited to learn them by putting them in the same sentence and so on. Next, while being scanned in the fMRI, participants were shown a series of single words -- some of which had been studied in the word pairings and some of which had not. Participants were asked to rate their memory for each word in terms of how confident they were that it was a word that they had studied earlier or not.
After each decision, participants were given a cue: the word was presented along with the word it was initially paired with. For about half of the familiar words, ie those that subjects recalled learning earlier, the pairing triggered rich detailed memories of the context -- such as the sentence they had made up to include both words -- in which the original pairing was learned. The fMRI scan showed hippocampus activity only when cues were used to retrieve memories.
"This study is important because it resolves a current debate on the role of the hippocampus in retrieving memories.
Some have argued it is the strength of the memory that matters most in retrieval. We have shown it is actually context that activates the hippocampus," explains Cohn. The findings also have direct relevance to understanding the type of memory problems found in Epilepsy or Alzheimer's, diseases in which patients have suffered damage to the hippocampus "Being able to characterize specific types of memory loss will lead to development of better clinical measures for diagnosis and monitoring of temporal-lobe dysfunction," she says
Other research team members from the University of Toronto's Department of Psychology are Mary Pat McAndrews, who also holds an appointment with the Krembil Neuroscience Centre, Ayelet Lahat and Morris Moscovitch. Programming and data analysis were done by Marilyne Ziegler, Sybille Schulz, Megan Walberg and Deborah Shwartz, all members of the University of Toronto's Department of Psychology. Research was funded by the Canadian Institutes of Health Research.
A team of researchers from the University of Toronto and the Krembil Neuroscience Centre at the University Health Network have shed some light on this mysterious process, discovering that the hippocampus, a brain region in the temporal lobe, is only involved when cues enable us to recall these rich memories.
"We used a technique called functional Magnetic Resonance Imaging (fMRI) that allows us to identify brain regions engaged during specific types of mental processes," says Melanie Cohn, a postdoctoral fellow in neuropsychology and lead author of the paper published online December 8 by the Proceedings of the National Academy of Sciences.
In the first stage of the study, healthy young adults were exposed to pairings of oddly unrelated words, such as "alligator" and "chair," and invited to learn them by putting them in the same sentence and so on. Next, while being scanned in the fMRI, participants were shown a series of single words -- some of which had been studied in the word pairings and some of which had not. Participants were asked to rate their memory for each word in terms of how confident they were that it was a word that they had studied earlier or not.
After each decision, participants were given a cue: the word was presented along with the word it was initially paired with. For about half of the familiar words, ie those that subjects recalled learning earlier, the pairing triggered rich detailed memories of the context -- such as the sentence they had made up to include both words -- in which the original pairing was learned. The fMRI scan showed hippocampus activity only when cues were used to retrieve memories.
"This study is important because it resolves a current debate on the role of the hippocampus in retrieving memories.
Some have argued it is the strength of the memory that matters most in retrieval. We have shown it is actually context that activates the hippocampus," explains Cohn. The findings also have direct relevance to understanding the type of memory problems found in Epilepsy or Alzheimer's, diseases in which patients have suffered damage to the hippocampus "Being able to characterize specific types of memory loss will lead to development of better clinical measures for diagnosis and monitoring of temporal-lobe dysfunction," she says
Other research team members from the University of Toronto's Department of Psychology are Mary Pat McAndrews, who also holds an appointment with the Krembil Neuroscience Centre, Ayelet Lahat and Morris Moscovitch. Programming and data analysis were done by Marilyne Ziegler, Sybille Schulz, Megan Walberg and Deborah Shwartz, all members of the University of Toronto's Department of Psychology. Research was funded by the Canadian Institutes of Health Research.
With Amino Acid, Mice Improve Memory After Brain Injury
ScienceDaily (Dec. 12, 2009) — Neurology researchers have shown that feeding amino acids to brain-injured animals restores their cognitive abilities and may set the stage for the first effective treatment for cognitive impairments suffered by people with traumatic brain injuries.
"We have shown in an animal model that dietary intervention can restore a proper balance of neurochemicals in the injured part of the brain, and simultaneously improves cognitive performance," said study leader Akiva S. Cohen, Ph.D., a neuroscientist at The Children's Hospital of Philadelphia.
The study appears December 7 in the online issue of the Proceedings of the National Academy of Sciences.
If these results in mice can be translated to human medicine, there would be a broad clinical benefit. Every 23 seconds, a man, woman or child in the United States suffers a traumatic brain injury (TBI). The primary cause of death and disability in children and young adults, TBI also accounts for permanent disabilities in more than 5 million Americans. The majority of those cases are from motor vehicle injuries, along with a rising incidence of battlefield casualties.
Although physicians can relieve the dangerous swelling that occurs after a TBI, there are currently no treatments for the underlying brain damage that brings in its wake cognitive losses in memory, learning and other functions.
The animals in the current study received a cocktail of three branched chain amino acids (BCAAs), specifically leucine, isoleucine and valine, in their drinking water. Previous researchers had shown that people with severe brain injuries showed mild functional
improvements after receiving BCAAs through an intravenous line.
BCAAs are crucial precursors of two neurotransmitters -- glutamate and gamma-aminobutyric acid, or GABA, which function together to maintain an appropriate balance of brain activity. Glutamate excites neurons, stimulating them to fire, while GABA inhibits the firing. Too much excitement or, too little, and the brain doesn't work properly. A TBI upsets the balance.
In particular, a TBI frequently damages the hippocampus, a structure deep in the brain involved in higher learning and memory. In the current study, the researchers found that an injury to the hippocampus reduced levels of BCAAs. Although overall levels of glutamate and GABA were unchanged, the loss of BCAAs disturbed the critical balance of neurotransmitters in the hippocampus, making some localized regions more excitable and others less excitable. Cohen's team tested the hypothesis that providing dietary BCAAs would restore the balance in neural response.
In this study, Cohen's study team first created standardized brain injuries in mice, and one week later compared the animals' conditioned fear response to that of uninjured mice. A week after receiving a mild electric shock in a specific cage, normal mice tend to "freeze" when placed in the same cage, anticipating another shock. The brain-injured mice demonstrated fewer freezing responses -- a sign that they had partially lost that piece of learning.
On the other hand, brain-injured mice that received a diet of BCAAs showed the same normal response as the uninjured mice. The BCAA cocktail had restored their learning ability.
In addition to the behavioral results, the team conducted electrophysiological experiments in slices of hippocampus from brain-injured and non-injured mice, and showed that BCAA restored a normal balance of neural activity. "The electrophysiological results were consistent with what we saw in the animals' functional recovery," said Cohen.
If the results in mice can be reproduced in people, patients with traumatic brain injuries could receive the BCAAs in a drink. Cohen suggests that BCAAs as a dietary supplement could have a more sustained, measured benefit than that seen when patients receive BCAAs intravenously, in which the large IV dose may flood brain receptors and have more limited benefits.
Although much work remains to be done to translate the finding into a therapy, Cohen expects to collaborate over the next year with other researchers in an early-phase clinical trial of dietary BCAAs in patients with mild to moderate TBI.
The National Institutes of Health provided funding for this study. Cohen's co-authors were Jeffrey Cole, Ph.D., Christina M. Mitala, Ph.D., Suhali Kundu and Itzhak Nissim, Ph.D., all of Children's Hospital; Jaclynn A. Elkind of the University of Pennsylvania; and Ajay Verma, M.D., Ph.D., of the Uniformed Services University of the Health Sciences, Bethesda, Md. Cohen and Nissim are also on the faculty of the University of Pennsylvania School of Medicine.
"We have shown in an animal model that dietary intervention can restore a proper balance of neurochemicals in the injured part of the brain, and simultaneously improves cognitive performance," said study leader Akiva S. Cohen, Ph.D., a neuroscientist at The Children's Hospital of Philadelphia.
The study appears December 7 in the online issue of the Proceedings of the National Academy of Sciences.
If these results in mice can be translated to human medicine, there would be a broad clinical benefit. Every 23 seconds, a man, woman or child in the United States suffers a traumatic brain injury (TBI). The primary cause of death and disability in children and young adults, TBI also accounts for permanent disabilities in more than 5 million Americans. The majority of those cases are from motor vehicle injuries, along with a rising incidence of battlefield casualties.
Although physicians can relieve the dangerous swelling that occurs after a TBI, there are currently no treatments for the underlying brain damage that brings in its wake cognitive losses in memory, learning and other functions.
The animals in the current study received a cocktail of three branched chain amino acids (BCAAs), specifically leucine, isoleucine and valine, in their drinking water. Previous researchers had shown that people with severe brain injuries showed mild functional
improvements after receiving BCAAs through an intravenous line.
BCAAs are crucial precursors of two neurotransmitters -- glutamate and gamma-aminobutyric acid, or GABA, which function together to maintain an appropriate balance of brain activity. Glutamate excites neurons, stimulating them to fire, while GABA inhibits the firing. Too much excitement or, too little, and the brain doesn't work properly. A TBI upsets the balance.
In particular, a TBI frequently damages the hippocampus, a structure deep in the brain involved in higher learning and memory. In the current study, the researchers found that an injury to the hippocampus reduced levels of BCAAs. Although overall levels of glutamate and GABA were unchanged, the loss of BCAAs disturbed the critical balance of neurotransmitters in the hippocampus, making some localized regions more excitable and others less excitable. Cohen's team tested the hypothesis that providing dietary BCAAs would restore the balance in neural response.
In this study, Cohen's study team first created standardized brain injuries in mice, and one week later compared the animals' conditioned fear response to that of uninjured mice. A week after receiving a mild electric shock in a specific cage, normal mice tend to "freeze" when placed in the same cage, anticipating another shock. The brain-injured mice demonstrated fewer freezing responses -- a sign that they had partially lost that piece of learning.
On the other hand, brain-injured mice that received a diet of BCAAs showed the same normal response as the uninjured mice. The BCAA cocktail had restored their learning ability.
In addition to the behavioral results, the team conducted electrophysiological experiments in slices of hippocampus from brain-injured and non-injured mice, and showed that BCAA restored a normal balance of neural activity. "The electrophysiological results were consistent with what we saw in the animals' functional recovery," said Cohen.
If the results in mice can be reproduced in people, patients with traumatic brain injuries could receive the BCAAs in a drink. Cohen suggests that BCAAs as a dietary supplement could have a more sustained, measured benefit than that seen when patients receive BCAAs intravenously, in which the large IV dose may flood brain receptors and have more limited benefits.
Although much work remains to be done to translate the finding into a therapy, Cohen expects to collaborate over the next year with other researchers in an early-phase clinical trial of dietary BCAAs in patients with mild to moderate TBI.
The National Institutes of Health provided funding for this study. Cohen's co-authors were Jeffrey Cole, Ph.D., Christina M. Mitala, Ph.D., Suhali Kundu and Itzhak Nissim, Ph.D., all of Children's Hospital; Jaclynn A. Elkind of the University of Pennsylvania; and Ajay Verma, M.D., Ph.D., of the Uniformed Services University of the Health Sciences, Bethesda, Md. Cohen and Nissim are also on the faculty of the University of Pennsylvania School of Medicine.
Wednesday, October 21, 2009
Researchers Optimizing Progesterone For Brain Injury Treatment
ScienceDaily (Oct. 21, 2009) — As doctors begin to test progesterone for traumatic brain injury at sites across the country, researchers are looking ahead to optimizing the hormone's effectiveness.
Two abstracts summarizing Emory research on progesterone are being presented at the 2009 Society for Neuroscience (SFN) meeting in Chicago.
A multisite phase III clinical trial called ProTECT III will begin to evaluate progesterone's effectiveness for treating traumatic brain injury early next year. The trial grows out of years of research by Donald Stein, PhD, Asa G. Candler Professor of Emergency Medicine at Emory School of Medicine, demonstrating that progesterone can protect damaged brain tissue. Stein is director of the Department of Emergency Medicine's Brain Research Laboratory.
One of the SFN abstracts reports on progesterone analogues that are more water-soluble. This work comes from Stein and his colleagues in collaboration with the laboratory of Dennis Liotta, PhD, Emory professor of chemistry.
Currently, the lack of water solubility limits delivery of progesterone, in that the hormone must be prepared hours ahead and cannot be kept at room temperature. Small chemical modifications may allow similar compounds with the same effects as progesterone to be given to patients closer to the time of injury.
According to the results, two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of traumatic brain injury.
The second abstract describes evidence that adding vitamin D to progesterone enhances the hormone's effectiveness when applied to neurons under stress in the laboratory. Like progesterone, vitamin D is a steroid hormone that is inexpensive, has good safety properties and acts on many different biochemical pathways.
The authors showed that a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death.
Two abstracts summarizing Emory research on progesterone are being presented at the 2009 Society for Neuroscience (SFN) meeting in Chicago.
A multisite phase III clinical trial called ProTECT III will begin to evaluate progesterone's effectiveness for treating traumatic brain injury early next year. The trial grows out of years of research by Donald Stein, PhD, Asa G. Candler Professor of Emergency Medicine at Emory School of Medicine, demonstrating that progesterone can protect damaged brain tissue. Stein is director of the Department of Emergency Medicine's Brain Research Laboratory.
One of the SFN abstracts reports on progesterone analogues that are more water-soluble. This work comes from Stein and his colleagues in collaboration with the laboratory of Dennis Liotta, PhD, Emory professor of chemistry.
Currently, the lack of water solubility limits delivery of progesterone, in that the hormone must be prepared hours ahead and cannot be kept at room temperature. Small chemical modifications may allow similar compounds with the same effects as progesterone to be given to patients closer to the time of injury.
According to the results, two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of traumatic brain injury.
The second abstract describes evidence that adding vitamin D to progesterone enhances the hormone's effectiveness when applied to neurons under stress in the laboratory. Like progesterone, vitamin D is a steroid hormone that is inexpensive, has good safety properties and acts on many different biochemical pathways.
The authors showed that a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death.
Monday, October 12, 2009
Key Mechanism In Brain Development Pinpointed, Raising Questions About Use Of Antiseizure Drugs
ScienceDaily (Oct. 12, 2009) — Researchers at the Stanford University School of Medicine have identified a key molecular player in guiding the formation of synapses — the all-important connections between nerve cells — in the brain. This discovery, based on experiments in cell culture and in mice, could advance scientists' understanding of how young children's brains develop as well as point to new approaches toward countering brain disorders in adults.
The new work also pinpoints, for the first time, the biochemical mechanism by which the widely prescribed drug gabapentin (also marketed under the trade name Neurontin) works. "We have solved the longstanding mystery of how this blockbuster drug acts," said Ben Barres, MD, PhD, professor and chair of neurobiology.
The study shows that gabapentin halts the formation of new synapses, possibly explaining its therapeutic value in mitigating epileptic seizures and chronic pain. This insight, however, may lead physicians to reconsider the circumstances in which the drug should be prescribed to pregnant women.
The paper, to be published online Oct. 8 in the journal Cell, looks at the interaction between neurons — the extensively researched nerve cells that account for 10 percent of the cells in the brain — and the less-studied but much more common brain cells called astrocytes. Much work has been done on how neurons transmit electrical signals to each other through synapses — the nanoscale electrochemical contact points between neurons. It is the brain's circuitry of some 100 trillion of these synapses that allow us to think, feel, remember and move.
It is commonly agreed that the precise placement and strength of each person's trillions of synaptic connections closely maps with that person's cognitive, emotional and behavioral makeup. But exactly why a particular synapse is formed in a certain place at a certain time has largely remained a mystery.
In 2005, Barres took a big step toward explaining this process when he and his colleagues discovered that a protein astrocytes secrete, called thrombospondin, is essential to the formation of this complex brain circuitry. Still, no one knew the precise mechanism by which thrombospondin induced synapse formation.
In this new study, Barres, lead author Cagla Eroglu, PhD, and their colleagues demonstrate how thrombospondin binds to a receptor found on neurons' outer membranes. The role of this receptor, known as alpha2delta-1, had been obscure until now. But in an experiment with mice, the scientists found that neurons lacking alpha2delta-1 were unable to form synapses in response to thrombospondin stimulation.
And when the researchers grew neurons in a dish that were bioengineered to overexpress this receptor, those neurons produced twice as many synapses in response to stimulation with thrombospondin than did their ummodified counterparts.
The new discovery about alpha2delta-1's key role in synapse formation carries important implications for understanding the cause of pain and of epilepsy and developing improved medications for these conditions.
It was already known that alpha2delta-1 is the neuronal receptor for gabapentin, one of the world's most widely administered medications.
Gabapentin is often prescribed for epilepsy and chronic pain, and its off-label use for other indications is widespread. Up to now, the molecular mechanism of gabapentin's action — what, exactly, it's doing to counter seizures or chronic pain — was unknown. But both syndromes may involve excessive numbers of synaptic connections in local areas of the brain.
In their new study, Barres and his colleagues found that when gabapentin was administered in developing mice, it bound to alpha2delta-1, preventing thrombospondin from binding to the receptor and, in turn, impeding synapse formation. Likewise, by blocking thrombosponin, gabapentin may reduce excess synapse formation in vulnerable areas of the human brain.
Barres noted that he and his colleagues found that gabapentin does not dissolve pre-existing synapses, but only prevents formation of new ones. That greatly diminishes gabapentin's potential danger to adults. In mature human brains, astrocytes ordinarily produce very little thrombospondin, and adult neurons don't form many new synapses, although some new synapses do continue to be formed throughout life — for example, in a part of the brain where new memories are laid down and at sites of injury to neurons, such as occurs after a stroke.
But the new findings raise questions about gabapentin's effect in situations where synapse formation is widespread and crucial, most notably in pregnancies. The vast bulk of the brain's synapses are formed during gestation and the very early months and years after birth. Because gabapentin easily crosses the placental barrier, it could potentially interfere with a fetus' rapidly developing brain just when global synapse formation is proceeding at breakneck speed.
"It's a bit scary that a drug that can so powerfully block synapse formation is being used in pregnant women," Barres said. "This potential effect on fetal brains needs to be taken seriously. Right now, doctors have the view that gabapentin is the safest anticonvulsant. There is no question that pregnant women with epilepsy who have been advised by their neurologists to continue their anticonvulsant treatment with gabapentin during their pregnancy should definitely remain on this drug until instructed otherwise. But there is no long-term registry being kept to track gabapentin-exposed babies. Our findings are saying that we need to be following up on these newborns so that their cognitive performance can be studied as they grow older."
Eroglu, then a postdoctoral researcher in Barres' laboratory, is now an assistant professor of cell biology at Duke University in Durham, N.C. Other Stanford co-authors were Nicola Allen, PhD; Michael Susman; Nancy O'Rourke, PhD; Chan Young Park, PhD; Engin Ozkan, PhD; Chandrani Chakraborty; Sara Mulinyawe; Andrew Huberman; PhD; Eric Green, MD, PhD; Ricardo Dolmetsch, PhD; Christopher Garcia, PhD; and Stephen Smith, PhD. Funding was provided by the National Institute of Drug Addiction; the National Heart, Lung and Blood Institute; the National Institutes of Health; the Human Frontiers Scientific Program and a Helen Hay Whitney postdoctoral fellowship.
The new work also pinpoints, for the first time, the biochemical mechanism by which the widely prescribed drug gabapentin (also marketed under the trade name Neurontin) works. "We have solved the longstanding mystery of how this blockbuster drug acts," said Ben Barres, MD, PhD, professor and chair of neurobiology.
The study shows that gabapentin halts the formation of new synapses, possibly explaining its therapeutic value in mitigating epileptic seizures and chronic pain. This insight, however, may lead physicians to reconsider the circumstances in which the drug should be prescribed to pregnant women.
The paper, to be published online Oct. 8 in the journal Cell, looks at the interaction between neurons — the extensively researched nerve cells that account for 10 percent of the cells in the brain — and the less-studied but much more common brain cells called astrocytes. Much work has been done on how neurons transmit electrical signals to each other through synapses — the nanoscale electrochemical contact points between neurons. It is the brain's circuitry of some 100 trillion of these synapses that allow us to think, feel, remember and move.
It is commonly agreed that the precise placement and strength of each person's trillions of synaptic connections closely maps with that person's cognitive, emotional and behavioral makeup. But exactly why a particular synapse is formed in a certain place at a certain time has largely remained a mystery.
In 2005, Barres took a big step toward explaining this process when he and his colleagues discovered that a protein astrocytes secrete, called thrombospondin, is essential to the formation of this complex brain circuitry. Still, no one knew the precise mechanism by which thrombospondin induced synapse formation.
In this new study, Barres, lead author Cagla Eroglu, PhD, and their colleagues demonstrate how thrombospondin binds to a receptor found on neurons' outer membranes. The role of this receptor, known as alpha2delta-1, had been obscure until now. But in an experiment with mice, the scientists found that neurons lacking alpha2delta-1 were unable to form synapses in response to thrombospondin stimulation.
And when the researchers grew neurons in a dish that were bioengineered to overexpress this receptor, those neurons produced twice as many synapses in response to stimulation with thrombospondin than did their ummodified counterparts.
The new discovery about alpha2delta-1's key role in synapse formation carries important implications for understanding the cause of pain and of epilepsy and developing improved medications for these conditions.
It was already known that alpha2delta-1 is the neuronal receptor for gabapentin, one of the world's most widely administered medications.
Gabapentin is often prescribed for epilepsy and chronic pain, and its off-label use for other indications is widespread. Up to now, the molecular mechanism of gabapentin's action — what, exactly, it's doing to counter seizures or chronic pain — was unknown. But both syndromes may involve excessive numbers of synaptic connections in local areas of the brain.
In their new study, Barres and his colleagues found that when gabapentin was administered in developing mice, it bound to alpha2delta-1, preventing thrombospondin from binding to the receptor and, in turn, impeding synapse formation. Likewise, by blocking thrombosponin, gabapentin may reduce excess synapse formation in vulnerable areas of the human brain.
Barres noted that he and his colleagues found that gabapentin does not dissolve pre-existing synapses, but only prevents formation of new ones. That greatly diminishes gabapentin's potential danger to adults. In mature human brains, astrocytes ordinarily produce very little thrombospondin, and adult neurons don't form many new synapses, although some new synapses do continue to be formed throughout life — for example, in a part of the brain where new memories are laid down and at sites of injury to neurons, such as occurs after a stroke.
But the new findings raise questions about gabapentin's effect in situations where synapse formation is widespread and crucial, most notably in pregnancies. The vast bulk of the brain's synapses are formed during gestation and the very early months and years after birth. Because gabapentin easily crosses the placental barrier, it could potentially interfere with a fetus' rapidly developing brain just when global synapse formation is proceeding at breakneck speed.
"It's a bit scary that a drug that can so powerfully block synapse formation is being used in pregnant women," Barres said. "This potential effect on fetal brains needs to be taken seriously. Right now, doctors have the view that gabapentin is the safest anticonvulsant. There is no question that pregnant women with epilepsy who have been advised by their neurologists to continue their anticonvulsant treatment with gabapentin during their pregnancy should definitely remain on this drug until instructed otherwise. But there is no long-term registry being kept to track gabapentin-exposed babies. Our findings are saying that we need to be following up on these newborns so that their cognitive performance can be studied as they grow older."
Eroglu, then a postdoctoral researcher in Barres' laboratory, is now an assistant professor of cell biology at Duke University in Durham, N.C. Other Stanford co-authors were Nicola Allen, PhD; Michael Susman; Nancy O'Rourke, PhD; Chan Young Park, PhD; Engin Ozkan, PhD; Chandrani Chakraborty; Sara Mulinyawe; Andrew Huberman; PhD; Eric Green, MD, PhD; Ricardo Dolmetsch, PhD; Christopher Garcia, PhD; and Stephen Smith, PhD. Funding was provided by the National Institute of Drug Addiction; the National Heart, Lung and Blood Institute; the National Institutes of Health; the Human Frontiers Scientific Program and a Helen Hay Whitney postdoctoral fellowship.
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