In an exciting breakthrough, researchers have found that a specific gene, neuropilin2, plays a crucial role in the development of brain circuits, influencing both autism and epilepsy. This discovery could pave the way for future treatments to alleviate the symptoms of these often co-occurring conditions.
What’s Neuropilin2? Neuropilin2 is a gene that helps regulate how brain cells interact and form connections. It’s essential for adequately developing brain circuits, controlling the migration of specific neurons and maintaining their connections.
The Study Led by neuroscientist Viji Santhakumar at the University of California, Riverside, this study sheds light on how mutations in neuropilin2 can lead to behavioural changes associated with autism and an increased risk of seizures. The research published in Nature Molecular Psychiatry offers hope for new treatments targeting these conditions.
Key Findings
Gene Knockout Model: By creating a mouse model where the neuropilin2 gene was selectively deleted, researchers found that the absence of this gene disrupted neuron migration, leading to an imbalance in brain signals.
Behavioural Impact: This disruption resulted in autism-like behaviours and a higher risk of seizures.
Focus on Inhibitory Neurons: The study highlights the importance of inhibitory neurons, which help balance brain activity. Without neuropilin2, these neurons don’t migrate correctly, affecting brain function.
Future Implications Santhakumar and her team believe that understanding how neuropilin2 influences brain circuit formation could lead to targeted therapies for autism and epilepsy. By focusing on specific phases of neuron development, it might be possible to prevent these disorders if detected early.
Collaborative Effort This study is a collaboration between UC Riverside and Rutgers University, combining cutting-edge techniques to explore both behavioural and physiological aspects of brain function.
Why It Matters Autism and epilepsy often co-occur, and finding a common genetic link offers a new direction for research and treatment. This study advances our understanding of these conditions and underscores the importance of investigating genetic influences on brain development.
For more exciting updates on this research, keep an eye on future publications and advancements from UC Riverside and their collaborators.
This fascinating discovery brings us one step closer to improving the lives of those affected by autism and epilepsy. Stay tuned for more updates as this research progresses!
Excitatory neurons from mice’s brains are depicted in green, and PV inhibitory neurons are pictured in magenta. Cells in the deep hippocampus, which helps navigate space, are represented toward the left side of the image. Toward the right side, cells are defined in the visual cortex. Findings from Johns Hopkins Medicine may help scientists better understand the causes of autism, schizophrenia and epilepsy.
Neuroscientists from Johns Hopkins Medicine say they have determined how a brain cell surface molecule shapes certain neurons’ behaviour.
The research, which was published on October 2 in Nature, reveals how a molecule called the calcium-permeable (CP)-AMPA receptor suppresses a specific neuron’s ability to pay attention to specific external cues, such as your friend’s earrings. The study was conducted on genetically engineered mice. Understanding why some neurons are less “selective” about their response to certain cues may also help researchers study conditions such as schizophrenia, epilepsy, and autism, which are marked by the faulty processing of external cues and misfirings of neurons in the mammalian brain.
“We have found that the calcium-permeable subtype of AMPA receptors plays an additional role in suppressing the selectivity of a specific neuron,” says Dr. Ingie Hong, the first author and a neuroscience instructor at Johns Hopkins University School of Medicine. “Until now, the function of these particular receptors in the broader mammalian brain during everyday activities has been a mystery.”
AMPA receptors are critical to the fast transfer of information and memory formation in the brain, such as hearing and remembering a person’s name. The subtype of AMPA receptors in this study, CP-AMPA receptors, act as a “gate” that lowers the selectivity of parvalbumin (PV) neurons, which are inhibitory and thereby cast unselective inhibition to nearby neurons, the researchers say.
“Selective neurons will respond to something really specific, for example, your grandfather’s mustache, whereas less selective neurons will respond to different faces or people as well,” Hong says. “We’ve been looking for the mechanisms and molecules that control this specificity, or selectivity, and how it goes awry in conditions such as autism and epilepsy, where excitatory neurons can become overstimulated.”
The researchers also found that mutations of GluA2, a protein subunit within the CP-AMPA receptor, are associated with intellectual disabilities.
“Human mutations in the GluA2 subunit of the AMPA receptors, which regulates the calcium permeability of the receptor, can lead to intellectual disability and autism,” says senior author Huganir. “This suggests tight control of AMPA receptor calcium permeability is essential for human cognition.”
Specifically, the investigators focused on CP-AMPA receptors in two distinct areas of the brain, the visual cortex, where neurons process visual information, and the hippocampus, where neurons respond to “where you are, where you are headed, or where you have been,” Hong says.
To conduct their research, the scientists developed novel adeno-associated virus vectors to replace calcium permeable AMPA receptors with impermeable counterparts and express them in the mouse brain. They say they hope these vectors can help treat disorders that arise from AMPA receptor mutations in the future.
To map out PV neuron selectivity, the scientists used advanced imaging techniques to observe neuron structure and activity deep within genetically engineered mice brains while showing them video stimuli.
“In most cases, we found that these PV neurons, which are typically less selective, became more selective to visual stimuli as well as spatial location when we swapped out CP-AMPA receptors for impermeable molecules, making inhibitory neurons act more like excitatory neurons,” Hong says.
The researchers say the high amount of CP-AMPA receptors in PV neurons is well-conserved across many species of mammals, including humans.
“Making neuron inhibition less selective makes our neural circuits more efficient than species that don’t have this molecular feature,” Hong says. “It probably also means that our neural networks are more stable.”
Hong says the new research may also have implications for machine learning used in artificial intelligence.
“In machine learning, there are many computerized ‘artificial’ neurons that are trained to be very selective or less selective,” he says. “We’re trying to find how specific and less specific units can work together to give us smarter machines and smarter AI.”
This microscope image of the brain region called the hippocampus shows the protein targeted by cannabis-derived CBD, GPR55 (red), and brain cells (blue) that send their extensions out to form the layers seen in the image. The interconnected nature of the hippocampus makes it a significant site for the initiation and spread of seizures. Tsien et al, Courtesy of Cell Press
A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can be hijacked by disease to promote seizures.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
“The study also clarified, not just how CBD counters seizures, but more broadly, how circuits are balanced in the brain,” added Tsien. “Related imbalances are present in autism and schizophrenia so that the paper may have a broader impact.”
Disease-Causing Loop
The study results build on how each neuron “fires” to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell’s end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
Scientists at Gladstone Institutes reports new findings that could guide the development of better therapeutic strategies for Dravet syndrome and related conditions. Shown here are the study’s first authors, Eric Shao (left) and Che-Wei Chang (right). CREDIT Photo: Michael Short/Gladstone Institutes
Children with Dravet syndrome, a severe form of epilepsy that begins in infancy, experience seizures, usually for their entire life. They are at high risk of sudden unexpected death in epilepsy (SUDEP) and can also develop intellectual disability and autism. Available treatments typically fail to improve these symptoms.
The researchers previously discovered, in a mouse model of Dravet syndrome, that genetically removing the protein tau from the entire body during embryonic development reduces epilepsy, SUDEP, and autism-like behaviors. In the new study, they pinpoint the key cell type in the brain in which tau levels must be reduced to avoid these problems. They also show that lowering tau is still effective in mice when the intervention is delayed until after their birth.
“Our findings provide new insights into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain,” says Mucke, director of the Gladstone Institute of Neurological Disease. “They are also encouraging from a therapeutic perspective, since in humans, initiating treatment after birth is still more feasible than treating embryos in the womb.”
Tau is a promising therapeutic target not only for Dravet syndrome, but also for a variety of other conditions, including different types of epilepsy and some forms of autism, as well as Alzheimer’s disease and related neurodegenerative disorders.
Pinpointing the Crucial Brain Cells
A well-functioning brain depends on the correct balance between the activity of excitatory and inhibitory neurons—the former stimulate the activity of other neurons, while the latter suppress it. Dravet syndrome causes an imbalance between these types of cells, resulting in abnormally high and synchronized activity in brain networks that can manifest as seizures and other symptoms.
Mucke and his colleagues recently showed that removing tau from the entire brain changes the activities of both excitatory and inhibitory neurons, although in different ways. The current study aimed to determine whether it is more important to reduce tau in excitatory or inhibitory neurons.
For this purpose, the scientists used genetic tools to eliminate tau selectively from one or the other cell type in the Dravet mouse model. They found that removing tau from excitatory neurons reduced disease manifestations, whereas removing tau from inhibitory neurons did not.
“This means that tau production in excitatory neurons sets the stage for all these abnormalities to occur, including autistic behaviors, epilepsy, and sudden unexpected death,” says Mucke, who is also the Joseph B. Martin Distinguished Professor of Neuroscience and a professor of neurology at UC San Francisco.
Initiating Treatment after Birth
While the genetic approaches the scientists used to remove tau from specific cell types are effective and precise, they are not yet easy to use as a therapeutic intervention in humans. So, the team turned to a more practical option: global tau reduction in the brain with DNA fragments known as antisense oligonucleotides, or ASOs. The scientists delivered an anti-tau ASO into the brain of mice 10 days after birth and found that most symptoms of Dravet syndrome were gone 4 months later.
“We observed a robust reduction of SUDEP, seizure activity, and repetitive behaviors,” says Eric Shao, PhD, a scientist in Mucke’s lab and first author of the study.
In addition, the ASO treatment had no obvious side effects.
“We are excited about these findings, especially since another anti-tau ASO has already undergone a Phase I clinical trial in people with Alzheimer’s disease,” says Mucke. “It could be useful to consider this strategy also for Dravet syndrome and related conditions. However, defining the optimal timing for treatment initiation will be key, as the window of opportunity might be quite narrow.”
Although Alzheimer’s disease, epilepsy, and autism have diverse causes, they all seem to be associated with abnormally high ratios between excitatory and inhibitory neuronal activities—and this abnormality could potentially be fixed by tau-lowering therapeutics.
Still, a treatment based on anti-tau ASOs would involve repeated spinal taps, a procedure most people would rather avoid. Therefore, Mucke is partnering with Takeda Pharmaceuticals to develop small molecules that could reduce brain tau levels when administered as a pill.
The first clinical trial of a new dietary treatment for children and adults with severe forms of epilepsy, co-developed by UCL researchers and based on the ketogenic diet, has been successfully completed.
For the study, published in Brain Communications, clinicians evaluated the use of K.Vita®, (also known as Betashot), an oral liquid dietary supplement developed by UCL in collaboration with Royal Holloway, University of London, and Vitaflo International Ltd.
The ketogenic diet (KD) consists of high-fat, low-carbohydrate and adequate protein consumption and mimics the fasting state, altering the metabolism to use body fat as the primary fuel source. This switch from carbohydrates to fat for body fuel is known as ketosis.
It is widely used to treat drug resistant epilepsies. However, the highly restrictive diet, which can cause constipation, low blood sugar, and stomach problems, can have poor compliance and is not suitable for everyone. Some KD supplements are also known to be unappetising.
K.Vita is based on novel findings by UCL researchers*, who discovered a different underlying mechanism to explain why the KD is effective against epilepsy; in developing a new treatment, researchers also sought to reduce the adverse side effects caused by KD.
Corresponding author Professor Matthew Walker (UCL Queen Square Institute of Neurology) said: “The ketogenic diet has been used for 100 years to treat epilepsy, helping reduce seizures in both children and adults.
“It has long been thought the diet was effective due to its production of ketones**, however we now believe the increase in levels of the fatty acid, decanoic acid, also produced by the diet, may provide the powerful antiseizure effects.
“In this study we evaluated a newly developed medium chain triglyceride (type of dietary fat) supplement, designed to increase levels of decanoic acid, while also reducing the adverse side effects, and to be more palatable.”
For the feasibility trial, researchers wanted to establish participants’ tolerance (side effects such as bloating or cramps) to the treatment, acceptability (flavour, texture, taste) and compliance (how easy it is to use K.Vita at the advised quantity, as part of their daily diet).
As secondary outcomes, they also monitored the frequency of epileptic seizures or paroxysmal events (fits, attacks, convulsions) and whether ketone production was decreased.
In total, 35 children (aged 3 to 18) with genetically caused epilepsy and known to be unresponsive to drugs, and 26 adults with drug-resistant epilepsy*** (DRE), were given K.Vita liquid supplements (a drink), to be taken with meals. They were also asked to limit high-refined sugary food and beverages from their diets.
The trial lasted 12 weeks with K.Vita treatments increasing incrementally over time, taking into account individuals’ tolerance to the treatment.
In total, 23/35 (66%) children and 18/26 (69%) adults completed the trial i.e they were continuing to take K.Vita at 12 weeks. Gastrointestinal disturbances were the primary reason for discontinuation, and their incidence decreased over time
Over three-quarters of participants/caregivers reported favourably on sensory attributes, such as taste, texture and appearance, and ease of use.
In regards to the secondary outcomes, there was a mean 50% reduction in seizures or paroxysmal events, and fewer than 10% of people on the diet produced significant ketones.
Commenting on the findings, Professor Walker, who is also a consultant neurologist at the National Hospital for Neurology and Neurosurgery, said: “Our study provides early evidence of the tolerability and effectiveness of a new dietary supplement in severe drug-resistant epilepsies in adults and children and provides a further treatment option in these devastating conditions.
“It also offers an alternative, more liberal, diet for those who cannot tolerate or do not have access to ketogenic diets.”
He added: “While this study was not designed to include enough patients to fully assess the supplement’s effects on seizures, it is exciting to report that there was a statistically significant reduction in the number of seizures in the group overall after three months of treatment.
“Furthermore, high ketone levels were not observed in over 90% of the participants. This indicates that the effect of the diet was independent from ketosis; this is important because high ketone levels in the ketogenic diets contribute to both short- and longer-term side effects.”
First author, Dr Natasha Schoeler, Research Dietitian at UCL Great Ormond Street Institute of Child Health, commented: “This novel dietary approach for epilepsy management involves following the principles of a healthy balanced diet alongside use of K.Vita, allowing greater dietary freedom compared to ketogenic diets. Our approach also requires much less input from a specialist dietician than is required by traditional ketogenic diets, and so may allow more widespread access to people with drug-resistant epilepsy.”
Researchers say larger, controlled studies of K.Vita are now needed to determine the precise epilepsies and conditions in which the supplement is most effective.
We use cookies on our website to give you the most relevant experience by remembering your preferences and repeat visits. By clicking “Accept”, you consent to the use of ALL the cookies.
This website uses cookies to improve your experience while you navigate through the website. Out of these, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the ...
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.