Immune molecules guide communication in young neurons
Immune molecules known as the major histocompatibility complex I (MHCI) help the body identify viruses or other foreign invaders. Once the invaders have been identified, MHCI helps to signal other components of the immune system to minimize the spread of infection to other cells. Research conducted in the past few years revealed a surprising discovery – these immune molecules also influence the development of the brain. Now, in a study funded by Autism Speaks, Kimberley McAllister, Ph.D. and her lab at the University of California, Davis, have demonstrated an important way that MHCI influences brain development by controlling the formation of synapses, or the connections between neurons, early in development.
Several different types of molecules have been shown to help instigate the formation of new synapses. MHCI proteins were known to be involved in later stages of brain development when little-used synapses disappear in favor of the more frequently-used connections between neurons. Dr. McAllister and her colleagues studied brain tissue from normal and genetically-altered mice with altered levels of MHCI protein on the cell surface. Using this model, the research team was able to assess the involvement of MHCI in cell-cell communication in synapse formation throughout development.
The team found that MHCI was indeed involved in establishing synapses early in the development of the cerebral cortex—the wrinkled outer envelope of brain tissue that is most involved in thinking, feeling and action planning. The effects of MHCI on synapse number were greatest early in development and those changes persisted into adulthood.
The research team also showed that MHCI regulates the balance of excitation versus inhibition in synapses. Over-excitation at the synapse has been found repeatedly in studies of brain connectivity and function in autism. “Our findings are consistent with the idea that MHCI proteins during early cortical development could alter cortical connectivity and the balance of excitation and inhibition, pathologies characteristic of several developmental disorders, including autism”, says Dr. McAllister.
Bradford Elmer, a graduate student in the McAllister lab, and one of Autism Speaks’ Weatherstone fellows, was a co-author on this paper. Mr. Elmer is concentrating on the role of MHCI proteins in the developing brain for his doctoral thesis. “Most of the work in our lab had manipulated MHCI proteins in cultured neurons, but I wanted to know whether it affected neuronal connectivity in the intact brain. We expected to see synaptic changes in the first post-natal week, but we were surprised to see that these changes are maintained into adulthood. It is especially interesting that the most dramatic changes in connectivity were during the early stages of brain development and plasticity. If immune dysregulation or a particular immune-sensitive genetic background is involved in autism, this provides a potential mechanism for environmental insults to alter brain development and cognition specifically during this critical period of development.”
As Dr. McAllister notes, “Because many environmental factors that may contribute to ASD impact immune responses, it will be important to determine which, if any, of these systemic immune responses alters MHCI molecules on neurons.” This type of discovery also has the potential to speed translational research. The effects of MHCI on establishing synapses offer a novel pathway to target for the development of treatments for ASD.
Although we do not yet have evidence to draw conclusions between immune responses and cortical connectivity, this report lays the foundation for making sense of a disparate collection of findings surrounding immune responses and brain development. Dr. McAllister cautions, “Despite our excitement about the potential for MHCI to mediate some of the effects of neurodevelopmental disorders, it is too early to make any inferences about how infection, in particular, might impact this pathway….. if it does at all. Our research is now focusing on trying to determine whether systemic immune responses during early development alter MHCI levels and synaptic connectivity in the brain.”