Interferon-Driven Neural Circuit Navigators

By Madison Dee

Microglia, the immune cells of the brain, take on the role of fighting infections and getting rid of debris. However, new research has revealed another crucial role they play during early brain development. A recent study, titled “Type-I-interferon-responsive microglia shape cortical development and behavior”, uncovers specific subsets of these cells called interferon-responsive microglia (IRMs). They are engaged in reshaping the brain’s neural circuits during a crucial developmental stage. The intriguing finding is that this behavior is driven by type I interferons (IFN-I), signaling molecules usually involved in antiviral responses. 

The study shows that IRMs appear during an important stage of brain development when the brain is still undergoing structural changes. The microglia are activated by IFN-I signaling and they engulf whole neurons that are stressed or show DNA damage, this process is also known as phagocytosis. It is essential for maintaining a healthy brain environment, as it helps remove harmful cells that could potentially disrupt brain development. When the researchers blocked IFN-I signaling in mice, microglia lost their ability to break down engulfed cells. This leads to an accumulation of neurons with double-strand DNA breaks, indicating cellular stress.  

Due to the discovery of microglia responding to IFN-I signaling by engulfing neurons, there are significant implications for understanding neurodevelopmental disorders. Let’s say the pathway is disrupted and this leads to a buildup of damaged neurons. This in turn could affect the brain’s ability to properly form neural connections. This problem could contribute to conditions like autism, schizophrenia, and neurodegenerative diseases. The study also suggests that processes driven by microglia help maintain the balance between different neurons. This balance is between excitatory neurons–which stimulate neurons–and inhibitory neurons–which restrain neurons. 

As IFN-I signaling is important when guiding microglia’s behavior, future research could focus on what triggers this response and how it supports healthy brain development. Researchers could explore whether environmental factors, such as viral infections, can influence the appearance of IRMs. Additionally, there may be therapeutic potential in targeting IFN-I signaling to treat microglial dysfunction conditions. By researching the link between microglia and IFNI-I when it comes to brain development, scientists can discover new pathways of neuro-related disorders. 

Q&A with Dr. Caroline Escoubas: 

Q: How did collaborations, potentially with Dr. Nowakowski, add to this study? 

A: Collaborations in general were absolutely key to this study! Science is not done in a bubble and in order to expand the scope of our story and expand our understanding of this mechanism we had to reach out to colleagues working on different areas of neuroscience. Our collaborators have contributed by giving us different mice models (to target microglia specifically for example), tissue samples (Alzheimer’s disease mice brains or covid-19 infected mice brains for example), by sharing with us their expertise (in the biology of dsDNA breaks for example). In the case of Dr Nowakowski, he was instrumental in the early stages of the project led by the co-first author Dr Leah Dorman. He helped train Leah in the single-cell sequencing analysis (which is the data you can find in Figure1 of the paper, where she identified the IRMs signature) and provided valuable input in that analysis.

Q: What were the biggest challenges you faced in this study and how did you overcome them?

A: I would say one major challenge in this project was to convince ourselves and others that our findings were real! Indeed, it was highly surprising when Leah identified a Type I interferon-responsive microglia population during physiology. To validate this initial exciting observation, we ended up studying these microglia in many different ways (by transcriptomics, immunofluorescence imaging, flow cytometry, using gain of function and loss of function approaches) and these experiments were done over a couple of years by different people (Leah, Phi, Christian, myself). Similarly, it was previously unknown that type I interferon signaling could modulate phagocytosis so we also used different techniques (in vitro, flow cytometry, imaging, etc) to study this effect. 

Q: The article states, "Taken together, these data suggested that IFN-I signaling may promote the elimination of neurons that had accumulated DNA damage." How does whisker elimination cause DNA damage/double-stranded breaks in neurons?  

A: Your question is a fantastic one! We have been asking ourselves the same question for some time now. This is something we did not address in this paper but it is definitely a question I am actively following up on now. One hypothesis we are exploring is that whisker deprivation leads to loss of sensory input to the corresponding neurons in the barrel cortex which probably leads to altered neuronal connectivity and firing. Several publications (cited in our paper) suggest that dsDNA breaks in neurons could be caused by neuronal activity. We are therefore looking at how whisker deprivation impacts neuronal activity and whether this correlates with the presence of dsDNA breaks.

Read the original article at: https://www.sciencedirect.com/science/article/pii/S0092867424001867?via%3Dihub.

Schema representing the main findings of the paper.