Three-dimensional reconstruction of electron microscopic images showing a synaptic spine (blue) of a new neuron (pink), which forms a synapse with another neuron (light blue), engulfed by microglia (green) in the adult mouse olfactory bulb CREDIT © 2022 Kurematsu et al. Originally published in Journal of Experimental Medicine.

A research group led by Kazunobu Sawamoto, a professor at Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences and National Institute for Physiological Sciences, and Chihiro Kurematsu, a fourth-year student at Nagoya City University School of Medicine, has elucidated the mechanism that controls synaptic pruning of new neurons in the adult brain.

In the mammalian brain, neural stem cells exist even after birth, and new neurons are produced. As these new neurons mature, they form connections called synapses with existing neurons to create functional neural circuits. For the brain to develop and function normally, it is important to maintain an appropriate number of synapses, but the mechanism to regulate the number of synapses has not been fully understood. Cells called microglia, which exist near nerve cells, play an important role in this process. Microglia can “eat” (phagocytose) dead cells and are also known to digest extra synapses during development. However, it was unknown how new neurons in the adult brain eliminate extra synapses during maturation.

Sawamoto’s group focused on phosphatidylserine (PS), a molecule that usually resides inside the cell membrane, but is found on the external surface of dead cells or developing synapses, where it is recognized by microglia. First, the researchers used an electron microscope to examine the microglia in detail and observed that microglia actually engulf synapses. Next, they examined the localization of PS and found that PS is exposed outside the cell membrane at synapses in the adult mouse brain, especially at less active synapses.

“To study whether microglial PS detection is important for synaptic pruning and normal neuron maturation in the adult brain, we needed to see what happens when PS is masked in living adult mice,” Sawamoto said.

Finally, they generated genetically modified mice in which PS outside the cell membrane was masked by a protein, and observed microglia and synapses. As a result, they found that in these mice, microglia could not eat synapses properly, resulting in extra synapses left behind.  Furthermore, neurons in these mice showed electrophysiological abnormalities. These results indicate that the synaptic pruning of newborn neurons by microglia is PS-dependent in the adult brain, and that this mechanism is important for the correct maturation of newborn neurons.

Recent studies have shown that new neurons are also produced in the human brain during the neonatal period, and microglial synaptic pruning is believed to be important for postnatal brain development.

“We hope that investigating PS-dependent synaptic elimination in mouse models of brain diseases will lead to the development of new therapeutic strategies for human pathological conditions such as autism, where abnormalities in microglia and synaptic density have been observed,” said Kurematsu.

This is Dr. Gnanathusharan Rajendran of University of Strathclyde. CREDIT University of Strathclyde

Young autistic people may find it difficult to multitask because they stick rigidly to tasks in the order they are given to them, according to research led by an academic at the University of Strathclyde.

The study also found that difficulty with ‘prospective memory’- remembering to carry out their intentions- may contribute to the challenges they face.

The researchers presented the pupils with a series of tasks, such as collecting and delivering a book and making a cup of hot chocolate, to be carried out within a time limit of eight minutes. These activities were carried out in a computer-generated virtual environment.

They found that the pupils did not appear to deviate from the order in which the tasks were listed, although doing so could have saved them time. They also broke several rules for the tasks, notably only being allowed to go up one staircase and down another.

An equal number of pupils with and without autism) took part in the study. The researchers will be exploring further the causes of the pupils’ problems with multitasking, in areas such as planning, memory, time pressure and inhibitory control.

Dr Gnanathusharan Rajendran, a lecturer in Psychology at Strathclyde, led the research, which also involved the University of Edinburgh and Liverpool John Moores University. He said: “Our research offers a real insight into the problems young people with autism have with multitasking and points the way to further investigation for possible solutions. By using, for the first time, a virtual environment, we have been able to examine what may lie behind these problems more closely than might be possible in a real-world setting.

“The pupils with autism achieved tasks when they were given to them singly but difficulties emerged when they were asked to interleave the tasks with each other. There was no difference in the time taken by the groups but the pupils with autism completed fewer tasks.

“The exercise could help to deal with these multitasking problems. The tasks or their environment could be changed to see if there is any influence on the outcomes and they could also be a tool for teaching and training.”###

New research in mice has identified neurons in the brain that influence competitive interactions between individuals and that play a critical role in shaping the social behaviour of groups. Published in Nature by a team led by investigators at Massachusetts General Hospital (MGH), the findings will be useful not only for scientists interested in human interactions but also for those who study neurocognitive conditions such as autism athat are characterized by altered social behaviour.

“Social interactions in humans and animals occur most commonly in large groups, and these group interactions play a prominent role in sociology, ecology, psychology, economics and political science,” says lead author S. William Li, an MD/PhD student at MGH. “What processes in the brain drive the complex dynamic behaviour of social groups remains poorly understood, in part because most neuroscience research thus far has focused on the behaviours of pairs of individuals interacting alone. Here, we were able to study the behaviour of groups by developing a paradigm in which large cohorts of mice were wirelessly tracked across thousands of unique competitive group interactions.”

Li and his colleagues found that the animals’ social ranking in the group was closely linked to the results of the competition, and by examining recordings from neurons in the brains of mice in real-time, the team discovered that neurons in the anterior cingulate region of the brain store this social ranking information to inform upcoming decisions.

“Collectively, these neurons held remarkably detailed representations of the group’s behaviour and their dynamics as the animals competed together for food, in addition to information about the resources available and the outcome of their past interactions,” explains senior author Ziv M. Williams, MD, a neurosurgical oncologist at MGH. “Together, these neurons could even predict the animal’s own future success well before competition onset, meaning that they likely drove the animals’ competitive behaviour based on whom they interacted with.”

Manipulating the activity of these neurons, on the other hand, could artificially increase or decrease an animal’s competitive effort and therefore control its ability to successfully compete against others. “In other words, we could tune up and down the animal’s competitive drive and do so selectively without affecting other aspects of their behaviour such as simple speed or motivation,” says Williams.

The findings indicate that competitive success is not simply a product of an animal’s physical fitness or strength, but rather, is strongly influenced by signals in the brain that affect the competitive drive. “These unique neurons are able to integrate information about the individual’s environment, social group settings, and reward resources to calculate how to best behave under specific conditions,” says Li.

In addition to providing insights into group behaviour and competition in different sociologic or economic situations and other settings, identifying the neurons that control these characteristics may help scientists design experiments to better understand scenarios in which the brain is wired differently. “Many conditions manifest in aberrant social behaviour that spans many dimensions, including one’s ability to understand social norms and to display actions that may fit the dynamical structure of social groups,” says Williams. “Developing an understanding of group behaviour and competition holds relevance to these neurocognitive disorders, but until now, how this happens in the brain has largely remained unexplored.” 

About 1 in 44 children in the U.S. are diagnosed with autism by the age of 8, according to the 2018 Centers for Disease Control and Prevention surveillance. How a child’s DNA contributes to the development of autism has been more of a mystery. Recently, clinicians and scientists have looked more closely at new, or de novo, DNA changes, meaning they only are present in affected individuals but not in the parents. Researchers have seen that these changes could be responsible for about 30% of autism. However, which de novo variants play a role in causing autism remains unknown.

Researchers at Baylor College of Medicine and Texas Children’s Hospital have taken a new approach to looking at de novo autism genetic variants. In this multi-institutional study published in the journal Cell Reports, they applied sophisticated genetic strategies in laboratory fruit flies to determine the functional consequences of de novo variants identified in the Simons Simplex Collection (SSC), which includes approximately 2,600 families affected by autism spectrum disorder. Surprisingly, their work also allowed them to uncover a new form of rare disease due to a gene called GLRA2. 

“Autisms include complex neurodevelopmental conditions with impairments in social interaction, communication and restricted interests or repetitive behaviors. In the current study, we initiated our work based on information from a cohort of autism patients in the SSC whose genomes and those of their families had been sequenced,” said co-corresponding author Dr. Shinya Yamamoto, assistant professor of molecular and human genetics and of neuroscience at Baylor and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s. “Our first goal was to identify gene variants associated with autism that had a detrimental effect.”

The team worked with the fruit fly lab model to determine the biological consequences of the autism –associated variants. They selected 79 autism variants in 74 genes identified in the SSC and studied the effect of each autism –linked gene variant compared to the commonly found gene sequence (reference) as a control, from three different perspectives.

Co-first author, Dr. Paul Marcogliese, postdoctoral fellow in Dr. Hugo Bellen’s lab, coordinated the effort on knocking out the corresponding fly gene, and examining their biological functions and expression patterns within the nervous system. They then replaced the fly gene with the human gene variant identified in patients, or the reference sequence, and determined how it affected biological functions in the flies.

Working with fruit flies carrying either the reference human gene or the variant forms, co-first author Dr. Jonathan Andrews, postdoctoral fellow in Dr. Michael Wangler’s lab at Baylor, was the point person investigating how these gene variants affected fly behavior. As autism patients exhibit patterns of repetitive behavior as well as changes in social interaction, he evaluated the effect of the patient variants on an array of social and non-social fly behaviors, such as courtship and grooming. “It’s interesting to see that manipulation of many of these genes also can cause behavioral changes in the flies,” Andrews said. “We found a number of human genes with autism variants that altered behavior when expressed in flies, providing functional evidence that these have functional consequences.”

The third approach involved overexpressing the genes of interest in different tissue types in fruit flies. Co-first authors Samantha Deal and Michael Harnish, two graduate students in Baylor’s Graduate Programs in Developmental Biology and Genetics and Genomics, respectively, working in Dr. Yamamoto’s lab, headed these studies. “While some gene variants may lead to conditions because they produce defective proteins, others may lead to disease because they cause overabundance or aberrant function of a particular protein, which can disrupt biological processes. We investigated whether overexpressing gene variants found in individuals with autism might explain the detrimental effect for some of these genes,” Deal said.

Altogether, the team generated more than 300 fly strains in which they conducted functional studies of human gene variants associated with autiusm . Their screen elucidated 30 autism -linked variants with functional differences compared to the reference gene, which was about 40% of the genes for which they were able to perform a comparative functional assay.

“Some of the variants we studied had functional consequences that were moderately or clearly predicted to be disruptive, but other variants were a surprise. Even the state-of-the-art computational programs couldn’t predict they would have detrimental effects,” said Yamamoto. “This highlights the value of using multiple, complementary approaches to evaluate the functional consequences of genetic variants associated with autism or other conditions in a living animal. Our fruit fly approach is a valuable tool to investigate the biological relevance of gene variants associated with disease.”

In addition, the wealth of data generated by the researchers revealed gene variants not previously connected with other neurodevelopmental diseases and uncovered new aspects of the complexity of genetic diseases.

“GLRA2 was one gene we specifically focused on to follow up,” Dr. Ronit Marom, assistant professor of molecular and human genetics at Baylor and lead clinician of this work said. “We identified 13 patients, five males and eight females, carrying rare variants of this X-linked gene that had not been established as a neurological disease gene before. Furthermore, males and females carried variants with different types of functional consequences and the spectrum of neurological characteristics among these 13 patients was different between the two groups. For instance, many of the boys carried loss of function variants and had autism , while the girls did not. They mainly presented with developmental delay as the main characteristic of their condition, and carried gain of function variants.”

“The picture that emerges is that autism may not be one disorder involving many genes. It may actually be hundreds of genetic disorders, like those caused by certain GLRA2 variants,” said Wangler, assistant professor of molecular and human genetics at Baylor and co-corresponding author of the work. “We think that this information is important to physicians seeing patients with autism .”