New Research Suggests Synaptic Plasticity is More Autonomous than Previously Thought

How is the development of the brain altered by the absence of microglia — immune cells that reside in the central nervous system?

That is the central question Thomas ‘Chris’ Brown, PhD, a postdoctoral associate in the Department of Translational Neurosciences (TNS), and his graduate advisor, Aaron McGee, PhD, professor of TNS at the University of Arizona College of Medicine – Phoenix, asked through a study recently published in Nature Neuroscience.

Their work analyzed the role of microglia in the development of visual circuitry in mouse models and discovered the unexpected — microglia deficiency did not have as profound an effect as prior studies suggested.

“For more than a decade, some neuroscientists have believed that microglia play critical roles in governing the function of neurons in the developing and mature brain. It has been proposed that microglia alter the connectivity between neurons by phagocytosing or ‘eating’ synapses,” Dr. McGee explained.

Conversely, the idea that microglia are also critical for removing “unwanted” synapses has gained widespread acceptance.

“Synapses connect neurons in the brain, allowing them to communicate with neurotransmitters. Neurons throughout the brain are continuously adding and pruning synapses as sensory input is received and committed to hardwired circuitry. This process is especially important during ‘critical periods’ of heightened plasticity in postnatal and childhood development,” Dr. McGee said. This partial reorganization of synaptic connectivity is central to the understanding of how a person’s brain adapts with life experience, including learning and memory. 

“Therapies that enhance or suppress the capacity for neuroplasticity are an unmet and potentially transformative clinical need applicable to a broad range of neurodevelopmental and neurodegenerative disorders. We wanted to know if microglia regulate plasticity in neural circuitry,” said Dr. McGee. 
Their work, which was conducted along with researchers from the University of Louisville School of Medicine, analyzed how the circuitry of the visual system adapts with visual experience during development. 

Much of the plasticity in this circuitry requires vision. So, Dr. Brown and colleagues utilized a research-grade drug to block an essential survival signal for microglia, causing these brain cells to disappear within a few days.

“Interestingly, removing microglia through the entire period of maturation for visual function didn’t alter any aspect of visual circuitry or function we examined,” Dr. McGee said.

First, the investigative team, including Bart Borghuis, PhD, professor at the University of Louisville, tested the function of neurons throughout the visual system from the eyes to the brain. Remarkably, very little was changed without microglia present. 

Then, Cecillia Attaway, a graduate student at the University of Louisville, determined that abolishing microglia did not affect visual acuity in mouse models. She and Dr. Borghuis independently measured the function of the eye, and it was normal as well.

These findings were extended by Dana Oakes, an MD-PhD student at the University of Louisville, who examined the organization of the visual thalamus — the principal conduit of information from the eye to the brain — and it was normal. 

Last, by using a custom-built microscope for imaging the function of hundreds of neurons in the visual cortex, Dr. Brown determined that the impact of abolishing microglia was undetectable. 

Dr. McGee, who led the research, noted, “We believe that these new findings may help refocus our understanding of how neurons self-govern their capacity for neuroplasticity.” 

Future work from Dr. McGee’s lab will investigate how changes to the environment surrounding neurons regulates neuroplasticity and limits recovery from the childhood visual disorder amblyopia.