By: PTI | New Delhi | Published: April 6, 2018
Faulty brain coordination behind attention disorders
Discordance between two brain regions could lead to attention deficit disorders, including schizophrenia, bipolar disorder and major depression, a study has found. People with attention deficits have difficulty focusing and often display compulsive behavior. Researchers from Case Western Reserve University in the US suggest these symptoms could be due to dysfunction in a gene ErbB4 that helps different brain regions communicate.
maintain healthy neurotransmitter levels in the brain. In a study published in the journal Neuron, researchers showed mice lacking ErbB4 activity in specific brain regions performed poorly on timed attention tasks. The mice struggled to pay attention and remember visual cues associated with food. Neuroscientists describe the kind of thought-driven attention required for the tasks as “top-down attention.”
Top-down attention is goal-oriented, and related to focus. People who lack efficient top-down attention are at a higher risk for attention deficit hyperactivity disorder (ADHD). The study is the first to connect ErbB4 to top-down attention. “The results reveal a mechanism for top-down attention, which could go wrong in attention disorders,” said Lin Mei, professor at Case Western Reserve University. “And since ErbB4 is a risk factor for schizophrenia, bipolar disorder, and major depression, the results provide insights into mechanisms of these disorders,” said Mei.
When the researchers attached probes to the mice to measure brain activity, they found mice without ErbB4 had brain regions that were acting independently, rather than together in synchrony. In particular, the researchers studied the prefrontal cortex – normally associated with decision-making – and the hippocampus – a region that supports memory. These two regions coordinate for a variety of brain tasks, including memory and attention.
IANS | New York Last Updated at April 6, 2018
Dysfunctional gene linked to ADHD, schizophrenia identified
Dysfunction in a gene that can lead to attention deficit hyperactivity disorder (ADHD) schizophrenia, bipolar disorder and depression has been identified.
People with attention deficits have difficulty focusing and often display compulsive behavior.
The study suggests that these symptoms could be due to dysfunction in ErbB4 gene, that helps different brain regions communicate.
ErbB4 is also a risk factor for psychiatric disorders and is required to maintain healthy neurotransmitter levels in the brain.
"And since ErbB4 is a risk factor for schizophrenia, bipolar disorder, and major depression, the results provide insights into mechanisms of these disorders," said Lin Mei, Professor Case Western Reserve University School of Medicine in Cleveland.
In the findings, published in the journal Neuron, researchers showed mice lacking ErbB4 activity in specific brain regions performed poorly on timed attention tasks.
The mice struggled to pay attention and remember visual cues associated with food. Neuroscientists describe the kind of thought-driven attention required for the tasks as "top-down attention".
Top-down attention is goal-oriented and related to focus. People who lack efficient top-down attention are at a higher risk for ADHD.
The study is the first to connect ErbB4 to top-down attention.
"The results reveal a mechanism for top-down attention, which could go wrong in attention disorders," Mei said.
The study found that when a protein (neuregulin-1) attaches to the ErbB4 receptor, it triggers a chain reaction that ultimately determines neurotransmitter levels in the prefrontal cortex and hippocampus.
Without ErbB4, neurotransmitter levels go awry.
The results showed that mice lacking ErbB4 have low levels of a particular neurotransmitter GABA, or gamma-aminobutyric acid, in the brain.
This further led to impaired top-down attention in the prefrontal cortex and impairs how the prefrontal cortex can efficiently coordinate with the hippocampus, a region that supports memory and attention.
EPILEPSY NEWS TODAY | JUNE 24, 2016
Molecule Miscommunication Could Shed Light on Epilspy, Other Neuro Disease
Researchers have discovered that a certain molecule responsible for communication between the brain and muscles, is also important for neuron to neuron communications. The finding could shed light on how dysfunction of the mechanism is related to neuropsychiatric disorders such as epilepsy, autism and schizophrenia.
Specifically, the study showed that lipoprotein receptor–related protein 4 (Lrp4) impairs the release of the neurotransmitter glutamate in the brain of mice, resulting in impaired locomotor activity, memory and resistance to seizure induction. The findings revealed a mechanism involved in the dysfunction of synapses (the juncture of two nerved cells) is associated with the neuropsychiatric illnesses.
The research paper “Lrp4 in astrocytes modulates glutamatergic transmission”, was published in Nature Neuroscience.
Glutamate is the most important excitatory neurotransmitter in the brain, with an essential role in neuron-to-neuron activation. In the study, researchers showed that the lipoprotein receptor–related protein 4 (Lrp4) in astrocytes, glial cells that have a role in neurodevelopment and regulation of communication between two neurons.
Epilepsy is a range of neurological conditions characterized by seizures. Two major hypothesis have been formulated for the mechanism of epilepsy development.
In the recent research, studies were conducted in mice without astrocyte-specific Lrp4. The mutant astrocytes suppressed the release of glutamate, through the enhancement of ATP release – the natural energy source of cells. Regulating ATP levels assist astrocytes to help regulate neurotransmitters.
“When you take LRP4 out of astrocytes, ATP levels released by those astrocytes go super high, which suppresses glutamate transmission,” said senior author Dr Lin Mei, chairman of the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Augusta University and Georgia Research Alliance Eminent Scholar in Neuroscience.
The deficient levels of glutamate led the mice to locomotor impairments, loss of spatial memory and resistance to seizure induction.
Researchers believe these results reveal a critical role for Lrp4 in not only the modulation of ATP release by astrocytes, but also in synaptic transmission.
Researchers concluded that the findings provide insight into the interaction between neurons and astrocytes for synaptic homeostasis and plasticity.
ScienceDaily June 23, 2016
Scientists learn more about how star-shaped brain cells help us learn
A molecule that enables strong communication between our brain and muscles appears to also aid essential communication between our neurons, scientists report.
On the surface of our numerous star-shaped brain cells called astrocytes, they have found the molecule LRP4 is important in ensuring healthy levels of a brain chemical that enables learning and memory, said Dr. Lin Mei, chairman of the Department of Neuroscience and Regenerative Medicine at the Medical College of Georgia at Augusta University and Georgia Research Alliance Eminent Scholar in Neuroscience.
The brain chemical, or neurotransmitter, is glutamate, the most important excitatory neurotransmitter in the brain, which essentially means it is passed between neurons to help one activate the next. It was known that astrocytes could regulate or modulate brain cell communication by adjusting levels of glutamate.
But now, the MCG scientists have shown that LRP4 is in those astrocytes, and that without it, glutamate release is dramatically reduced. Mice are intellectually impaired and have difficulty with movement, Mei said of the findings he characterizes as "unexpected." One benefit was protection from seizures because of the reduced excitability of neurons. Removing LRP4 from nearby neurons did not yield the same negative effects.
While much work remains, Mei and his colleagues believe the work published in the journal Nature Neuroscience provides new insight into the critical regulation of neurotransmitters that enable neurons to take action as well as potential therapeutic targets for one day helping individuals with intellectual disabilities.
Once made, glutamate gets passed from one neuron to the next via synapses, much like the arm of one neuron reaching out to hand something to the next. Dysfunction of synapses is associated with a host of neuropsychiatric disorders such as epilepsy, addiction, schizophrenia and autism.
Taking LRP4 out of the equation messes up the delicate balance, the scientists have found. Without it, levels of ATP, a natural energy source for cells that also inhibits glutamate release, also dramatically increase. In fact, regulating ATP levels is one way astrocytes help regulate the level of neurotransmitters, Mei said. But in this scenario, too much ATP translates to too little glutamate. Blocking the receptor ATP eventually activates ameliorates the negative impact that high levels had on the mice.
"When you take LRP4 out of astrocytes, ATP levels released by those astrocytes go super high, which suppresses glutamate transmission," Mei said.
Astrocytes are the most common of a type of brain cell called glial cells. In fact, astrocytes account for about half of all the cells in the brain, Mei said. While the brain actually has more glial cells than neurons, glial cells were long thought to provide only structural support to the neurons, much like cement supports a house. "That view has been changed and is changing," said Mei. Now it's clear that glial cells, like astrocytes, have a role in neurodevelopment and longer-term in regulating communication between two neurons.
In the neuromuscular juncture, Mei's lab found several years back that LRP4 on the muscle cell surface is a receptor for agrin, a protein that motor neurons release to direct construction of the nerve-muscle juncture. His lab later identified antibodies to LRP4 and agrin as new causes of myasthenia gravis. The new research indicates that release of ATP by astrocytes is also regulated by agrin signaling.
Scicasts Proteomics Nov 11, 2013
Research Uncovers New Cause for Muscle-Weakening Disease Myasthenia Gravis
An antibody to a protein critical to enabling the brain to talk to muscles has been identified as a cause of myasthenia gravis, researchers report.
The finding that an antibody to LRP4 is a cause of the most common disease affecting brain-muscle interaction helps explain why as many as 10 percent of patients have classic symptoms, like drooping eyelids and generalized muscle weakness, yet their blood provides no clue of the cause, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University.
"You end up with patients who have no real diagnosis," Mei said.
The finding also shows that LRP4 is important, not only to the formation of the neuromuscular junction – where the brain and muscle talk – but also maintaining this important connection, said Mei, corresponding author of the paper in The Journal of Clinical Investigation.
Mei and his colleagues first reported antibodies to LRP4 in the blood of myasthenia gravis patients in the Archives of Neurology in 2012. For the new study, they went back to animals to determine whether the antibodies were harmless or actually caused the disease. When they gave healthy mice LRP4 antibodies, they experienced classic symptoms of the disease along with clear evidence of degradation of the neuromuscular junction.
LRP4 antibodies are the third cause identified for the autoimmune disease, which affects about 20 out of 100,000 people, primarily women under 40 and men over age 60, according to the National Institutes of Health and Myasthenia Gravis Foundation of America, Inc.
An antibody to the acetylcholine receptor is causative in about 80 percent of patients, said Dr. Michael H. Rivner, MCG neurologist and Director of the Electrodiagnostic Medicine Laboratory, who follows about 250 patients with myasthenia gravis. Acetylcholine is a chemical released by neurons which act on receptors on the muscle to activate the muscle. More recently, it was found that maybe 10 percent of patients have an antibody to MuSK, an enzyme that supports the clustering of these receptors on the surface of muscle cells.
"That leaves us with only about 10 percent of patients who are double negative, which means patients lack antibodies to acetylcholine receptors and MuSK," said Rivner, a troubling scenario for physicians and patients alike. "This is pretty exciting because it is a new form of the disease," Rivner said of the LRP4 finding.
Currently, physicians like Rivner tell patients who lack antibody evidence that clinically they appear to have the disease. Identifying specific causes enables a more complete diagnosis for more patients in the short term and hopefully will lead to development of more targeted therapies with fewer side effects, Rivner said.
To learn more about the role of the LRP4 antibody, Mei now wants to know if there are defining characteristics of patients who have it, such as more severe disease or whether it's found more commonly in a certain age or sex. He and Rivner have teamed up to develop a network of 17 centres, like GR Medical Center, where patients are treated to get these questions answered. They are currently pursuing federal funding for studies they hope will include examining blood, physical characteristics, therapies and more.
Regardless of the specific cause, disease symptoms tend to respond well to therapy, which typically includes chronic use of drugs that suppress the immune response, Rivner said. However, immunosuppressive drugs carry significant risk, including infection and cancer, he said.
Removal of the thymus, a sort of classroom where T cells, which direct the immune response, learn early in life what to attack and what to ignore, is another common therapy for myasthenia gravis. While the gland usually atrophies in adults, patients with myasthenia gravis tend to have enlarged glands. Rivner is part of an NIH-funded study to determine whether gland removal really benefits patients. Other therapies include a plasma exchange for acutely ill patients.
National Institutes of Health NEWS RELEASES
Taming suspect gene reverses schizophrenia-like abnormalities in mice
NIH-funded study raises hope for recovery of some adult patients, despite early damage.
Scientists have reversed behavioral and brain abnormalities in adult mice that resemble some features of schizophrenia by restoring normal expression to a suspect gene that is over-expressed in humans with the illness. Targeting expression of the gene Neuregulin1, which makes a protein important for brain development, may hold promise for treating at least some patients with the brain disorder, say researchers funded by the National Institutes of Health.
Like patients with schizophrenia, adult mice biogenetically-engineered to have higher Neuregulin 1 levels showed reduced activity of the brain messenger chemicals glutamate and GABA. The mice also showed behaviors related to aspects of the human illness. For example, they interacted less with other animals and faltered on thinking tasks.
“The deficits reversed when we normalized Neuregulin 1 expression in animals that had been symptomatic, suggesting that damage which occurred during development is recoverable in adulthood,” explained Lin Mei, M.D., Ph.D, of the Medical College of Georgia at Georgia Regents University, a grantee of NIH’s National Institute of Mental Health (NIMH).
Mei, Dong-Min Yin, Ph.D., Yong-Jun Chen, Ph.D., and colleagues report on their findings May 22, 2013 in the journal Neuron.
“While mouse models can’t really do full justice to a complex brain disorder that impairs our most uniquely human characteristics, this study demonstrates the potential of dissecting the workings of intermediate components of disorders in animals to discover underlying mechanisms and new treatment targets,” said NIMH Director Thomas R. Insel, M.D. “Hopeful news about how an illness process that originates early in development might be reversible in adulthood illustrates the promise of such translational research.”
Schizophrenia is thought to stem from early damage to the developing fetal brain, traceable to a complex mix of genetic and environmental causes. Although genes identified to date account for only a small fraction of cases, evidence has implicated variation in the Neuregulin 1 gene. For example, postmortem studies have found that it is overexpressed in the brain's thinking hub, or prefrontal cortex, of some people who had schizophrenia. It codes for a chemical messenger that plays a pivotal role in communication between brain cells, as well as in brain development.
Prior to the new study, it was unclear whether damage caused by abnormal prenatal Neuregulin 1 expression might be reversible in adulthood. Nor was it known whether any resulting behavioral and brain deficits must be sustained by continued errant Neuregulin 1 expression in adulthood.
To find out, the researchers engineered laboratory mice to mimic some components of the human illness by over-expressing the Neuregulin 1 gene in the forebrain, comparable to the prefrontal cortex in humans. Increasing Neuregulin 1 expression in adult animals was sufficient to produce behavioral features, such as hyperactivity, social and cognitive impairments, and to hobble neural communications via the messenger chemicals glutamate and GABA.
Unexpectedly, the abnormalities disappeared when the researchers experimentally switched off Neuregulin 1 overexpression in the adult animals. Treatment with clozapine, an antipsychotic medication, also reversed the behavioral abnormalities. The researchers traced the glutamate impairment to an errant enzyme called LIMK1, triggered by the overexpressed Neuregulin 1 — a previously unknown potential pathological mechanism in schizophrenia.
The study results suggest that even if their illness stems from disruptions early in brain development, adult patients whose schizophrenia is rooted in faulty Neuregulin 1 activity might experience a reduction in some of the symptoms following treatments that target overexpression of the protein, say the researchers.
The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit http://www.nimh.nih.gov.
NEWS MEDICALLIFESCIENCES Jul 12 2012
Communication between brain and muscle cells is short-lived without LRP4 protein
Communication between the brain and muscle must be strong for us to eat, breathe or walk. Now scientists have found that a protein known to be on the surface of muscle cells must be present in both tissues to ensure the conversation is robust.
Scientists at the Medical College of Georgia at Georgia Health Sciences University have shown that without LRP4 in muscle cells and neurons, communication between the two cells types is inefficient and short-lived.
Problems with the protein appear to contribute to disabling disorders such as myasthenia gravis and other forms of muscular dystrophy. The MCG scientists reported finding antibodies to LRP4 in the blood of about 2 percent of patients with muscle-degenerating myasthenia gravis in Archives of Neurology earlier this year.
Scientists know that LRP4 plays an important role in the muscle cell, where it receives cues from the brain cell that it's time to form the receptors that will be enable ongoing communication between the two, said Dr. Lin Mei, Director of the GHSU Institute of Molecular Medicine and Genetics and corresponding author of the study in the journal Neuron.
However when Dr. Haitao Wu deleted LRP4 just from muscle cells, a connection - albeit a weak one - still formed between muscle and brain cells. The mice survived several days during which they experienced some of the same muscle weakness as patients with myasthenia gravis. "That's against the dogma," Mei said. "If LRP4 is essential only in the muscle cells, how could the mice survive?" When they totally eliminated LRP4, neuromuscular junctions never formed and the mice didn't survive.
Additional evidence suggests that LRP4 in the neurons is vital, said Wu, postdoctoral fellow and the study's first author. "When we knocked out the LRP4 gene in the muscles, there was some redundant function coming from the motor neuron, like a rescue attempt," he said. They documented the neuron reaching out to share LRP4 with the muscle cell. Unfortunately, the gesture was not sufficient.
"The nerve does not get the stop signal," Mei said, referencing images of too-long neurons that never got the message from the muscle that they have gone far enough. When they cut the elongated nerves, they found they didn't contain enough vesicles, little packages of chemical messengers that are the hallmark of brain cell communication. On the receiving end, muscle cells developed receptors that were too small and too few - hence, the tenuous communication network. "When LRP4 in the muscle is taken out, not surprisingly, the muscle has some kind of a problem," Mei said. "What was very surprising was that the motor neurons also have problems."
"The talk between motor neurons and muscle cells is very critical to the synapse formation and the very precise action between the two," Wu said. Mei's lab earlier established that the conversation goes both ways.
The scientists believe about 60 percent of the LRP4 comes from muscle cells, about 20 percent from brain cells - which helps explain why the brain's effort to share is insufficient - and the remainder from cells in spaces between the two. In addition to better explaining nerve-muscle communication, the scientists hope their findings will eventually enable gene therapy that delivers LRP4 to bolster insufficient levels in patients.
Other early and key players in establishing nerve-muscle conversation include agrin, a protein that motor neurons release to direct construction of the synapse, a sort of telephone line between the nerve and muscle. MuSK on the muscle cell surface initiates critical internal cell talk so synapses can form and receptors that enable specific commands will cluster at just the right spot.
Mei's lab reported in Neuron in 2008 that agrin starts talking with LRP4 on the muscle cell surface, then recruits the enzyme MuSK to join the conversation. LRP4 and MuSK become major components of the receptor needed for the muscle cell to receive the message agrin is sending.
The agrin-MuSK signaling pathway has been implicated in muscular dystrophy, a group of genetic diseases that lead to loss of muscle control because of problems with neurons, muscle cells and/or their communication. Some reports have implicated a mutant MuSK as a cause of muscular dystrophy and autoantibodies (antibodies the body makes against itself) to MuSK have been found in the blood of some patients.
K. Zhao, C. Shen, Y. Lu, Z. Huang, L. Li, C.D. Rand, J. Pan, X.D. Sun, Z. Tan, H. Wang, G. Xing, Y. Cao, W.C. Xiong, and L. Mei. Muscle Yap is a regulator of neuromuscular junction formation and regeneration. J. Neuroscience 37:3465-3477, 2017 (Cover). (Highlighted by Faculty 1000, DOI: 10.3410/f.727317699.793531488).
Arnab Barik, Yisheng Lu, Anupama Sathyamurthy, Andrew Bowman, Chengyong Shen, Lei Li, Wen-cheng Xiong and Lin Mei. Schwann Cells in Neuromuscular Junction Formation and Maintenance. Journal of Neuroscience 15 October 2014, 34 (42) 13892-13905
Arnab Barik, Yisheng Lu, Anupama Sathyamurthy, Andrew Bowman, Chengyong Shen, Lei Li, Wen-cheng Xiong and Lin Mei, LRP4 Is Critical for Neuromuscular Junction Maintenance. Journal of Neuroscience 15 October 2014, 34 (42) 13892-13905; (Cover)
Y. Zong, B. Zhang, S. Gu, K. Lee, J. Zhou, G. Yao, D. Figueiredo, K. Perry, L. Mei* and Rongsheng Jin*. Structural basis of agrin–LRP4–MuSK signaling. Genes & Development. 26:247-258, 2012 (Cover)