The results of research into brain development shortly after birth may provide new insights into how early life events can affect wiring patterns in the brain that, later in life may manifest as disease, and specifically disorders such as schizophrenia, epilepsy, and autism.

The murine study, by scientists at the Max Planck Florida Institute for Neuroscience, focused on chandelier cells (ChC), a type of inhibitory neurons in the cortical section of the brain, and neurons of the cholinergic system—one of the systems that monitor the environment and the internal state, and send signals to the rest of the brain to trigger memory and appropriate behaviors.

The results indicated that release of the neurotransmitter acetylcholine from the modulating cells initiates the branching, or arborization, of axons—the long, slender extensions of nerve cell bodies that transmit messages—on the chandelier cells in the cortex. This arborization then dictates how effective the cells in the cortex are at doing their job of using inhibitory effects to counter excitation in other cells.

The study, the team claimed, is the first to show that these two types of cells communicate very early in brain development. And while there is still a lot to learn about the impact of this cellular interaction in the postnatal brain, the results may help lead to a better understanding of how neurological diseases in adults may relate to early-life events.

“It’s known that abnormal early-life experiences can impact kids’ future sensation and behavior,” said Hiroki Taniguchi, PhD, who is now associate professor of pathology at the Ohio State University College of Medicine. “This finding may help explain that kind of mechanism.” The study provides new insight into brain development and brain pathology, Taniguchi continued. “It’s possible that during development, depending on animals’ experiences, this modulating system activity can be changed and, accordingly, the cortical circuit wiring can be changed.

Taniguchi completed the work with André Steinecke, PhD, and McLean Bolton, PhD, while he was an investigator at the Max Planck Florida Institute for Neuroscience. Taniguchi is senior author of the team’s paper, which is published in Science Advances, and titled, “Neuromodulatory control of inhibitory network arborization in the developing postnatal neocortex.”

The proper functioning of the cortex requires the exquisite assembly of neural circuits that comprise excitatory pyramidal neurons (PNs) and inhibitory interneurons (INs), the authors wrote. “A prominent feature of cortical circuit development is its dependency on early postnatal experiences with sensory stimuli as well as environmental/social events.”

The newly reported study specifically investigated the relationship between chandelier cells and the cortical neurons. “Both of these types of cells have been separately studied in the context of adult functions or modulations so far,” Taniguchi said. “The developmental role of cholinergic neurons in the brain wiring remains poorly understood.”

Chandelier cells are named for the spray of signal-transmitting synapses (called synaptic cartridges) at the branch terminals that resemble candles of a traditional chandelier, a pattern that gives them inhibitory control over hundreds of cells at a time.

“These cells have output control,” said first author Steinecke, who is now working at Neuway Pharma in Germany. “Chandelier cells can put a brake on excitatory cells and tell them they’re not ready to fire. As inhibitory cells, chandelier cells are thought to regulate waves of firing—which is important, because the waves contain information that is transmitted over large distances of the brain.”

Researchers studying the postnatal brain found that the neurotransmitter acetylcholine released from cholinergic system cells initiates the branching, or arborization, of axons on chandelier cells in the cortex—and that arborization dictates how effective chandelier cells are at doing their job of using inhibitory effects to counter excitation in other cells. The study is the first to show that these two types of cells, both implicated in such disorders as schizophrenia, epilepsy, and autism, communicate very early in brain development. [Hiroki Taniguchi and André Steinecke]

Previous post mortem studies had shown that the synaptic terminals located at the end of chandelier cell axons appear to be reduced in the brains of patients with schizophrenia. “This axonal ‘arbor’ being reduced suggests they don’t make as many connections to downstream targets, and the connections themselves are also altered and don’t work that well,” Steinecke said.

For their newly reported study the team used two techniques to observe chandelier cells during early-life brain development in mice: genetically targeting and using a dye to label and detect cells that differentiate into chandelier cells, and transplanting genetically manipulated cells back into animals shortly after birth. “This enabled us to watch brain development as it happens and manipulate conditions to test what the mechanisms are,” Taniguchi said.

The researchers first observed how chandelier cell axons develop their branching structures, noting that small protrusions emerging from axons were the first signs that branches would sprout. And they identified the chemical needed to start that sprouting process—the neurotransmitter acetylcholine (ACh), which is released by cholinergic system cells.

The interaction between the distant cell types was confirmed through a series of experiments, in which they found that knocking out receptors that bind to acetylcholine and decreasing activity of cholinergic neurons lessened branch development, and making cholinergic neurons more likely to fire led to more widespread branching. “Our findings that the degree of ChC axonal arborization is bidirectionally altered depending on the level of BF [basal forebrain] cholinergic neuronal activity suggest that the subcortical cholinergic system has potential to gradedly tune the wiring of ChCs during early postnatal stages,” the team noted. “Thus, the cholinergic system regulates inhibitory network arborization in the developing neocortex and may tune cortical circuit properties depending on early-life experiences.”

“The key is that we didn’t previously know how neuromodulatory systems regulate the cortical circuits—and both of them have been implicated in brain diseases,” Taniguchi said. “Now that we’ve found that cholinergic neurons could remotely impact cortical circuit development, especially cortical inhibitory signals, the question is what kind of environment or emotional state of change can impact cortical inhibitors’ development? We may want to see if we can find a link as a next step.”

Disturbances of cholinergic signaling and ChC wiring have been individually implicated in several brain disorders such as schizophrenia, epilepsy, and attention-deficit hyperactivity disorder,” the team further pointed out. “Our findings that the cholinergic system regulates ChC axonal arborization provide a potential link between these two defects … Disturbances of cholinergic signaling and ChC wiring have been individually implicated in several brain disorders such as schizophrenia, epilepsy, and attention-deficit hyperactivity disorder.” And while they acknowledged it’s not clear whether the cholinergic system generally affects inhibitory neuron axonal arborization, they stated, “ … our results provide a view that pathological conditions in cholinergic signaling can result in the aberrant formation of inhibitory circuits. Thus, our study proposes a novel direction to understanding the etiology of brain disorders caused by neuromodulatory defects.”

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