New research reveal how autism may alter synapse formation, pruning | Spectrum
Making Connections: In the second trimester of pregnancy, groups of neurons have formed identifiable synaptic connections in the human cortex.
Unpublished image courtesy of Li Zhou / University of California, San Francisco
Two new, unpublished studies, which were presented virtually at the Society for Neuroscience’s 2021 annual meeting, offer insights into synapse development: one maps the pathways of synapse formation across nine types, the other characterizes the earliest synapses that arise in the human brain.
The results could help researchers better understand how developmental changes can alter synaptic function and contribute to autism.
“To understand if something is different from neurotypical, you really have to know what is neurotypical,” says Sam Wang, professor of neuroscience at Princeton University and lead researcher on one of the new studies.
In all species, early brain development is defined by a period of abundant synapse formation, followed by a phase in which all unnecessary connections are truncated. Disturbance of both processes can explain some of the atypical developments in autism, but much about synaptic development remains unknown.
For example, when Wang and his colleagues began searching the literature to find out when cortical synapses are most common in development and whether this timing shows common patterns between species, they could not find any studies showing the full course of development from birth recorded into adulthood, says Henk-Jan Boele, a postdoctoral fellow in Wang’s laboratory, who presented the work. So they decided to plan this course themselves for as many species of mammals as they could find data.
Laws of Maturation:
Wang and Boele reduced their initial literature search to 130 studies that recorded synapse density at different time points for a variety of mammals, including humans, common marmosets, cats, rabbits, and mice. From these studies, the team extracted more than 16,000 unique data points for analysis and presentation by species.
Each species analyzed differs in the number of days it takes for the cortex to reach the highest synaptic density, the researchers found, but the time frame scales with the length of the animal’s gestational period. And in all of the species examined, the synaptic density peaked around one gestational period after birth.
“We didn’t expect that,” says Wang. “It’s like there is this universal law of scaling of cortical maturation.”
Other aspects of development did not lag behind the species: in human brains, cortical synapses mature first in the occipital lobe in the back of the brain and then progress steadily forward, while the cortical areas of macaques throughout the brain seemed to mature simultaneously – a climax in synaptic density at the same time and then steadily decreases as connections are cut.
Overlaying data points from autistic humans or autism model mice on the curves indicated that the condition is associated with a smaller decrease in synaptic density after the initial peak, which could be explained by insufficient pruning.
Wang and Boele next plan to study how early postnatal changes in the cerebellum, a region of the brain that some researchers suspect, facilitate cortical maturation and contribute to autism, shape these trajectories.
Growth curve: Most mammals studied achieve the highest synaptic density around one gestational period after birth.
Early signals:
The other new study looked at how synapses form in the first place.
The researchers injected a form of rabies virus into a single neuron in slices of post-mortem fetal brain tissue. The virus is transmitted to cells that synapse with the injected cell and cause it to fluoresce green, revealing its organization.
Most of the cells in these synaptic snapshots were arousing, the team found, and had immature electrical properties. The neurons also exhibited low levels of spontaneous calcium signals, which are believed to be necessary for the formation of new synapses during development.
“Synchronous activity can help [the cells] to recognize each other and to make connections, ”says study researcher Li Zhou, postdoctoral fellow in Arnold Kriegstein’s laboratory at the University of California, San Francisco, who presented the work.
Adding a serotonin receptor antagonist to cultured prenatal brain tissue dampened this spontaneous activity and, in a separate experiment, decreased the number of synapses in the tissue, the team found.
That means serotonin can manipulate neural activity at this stage of development, says Zhou.
In the future, Zhou plans to investigate how other types of receptors affect this calcium signal. He also plans to study these developmental mechanisms in organoids, which are easier to manipulate in the laboratory than fetal brain tissue.
Read more reports from the Society for Neuroscience’s 2021 Annual Virtual Meeting.
Quote this article: https://doi.org/10.53053/WMPH7503
