Immune cells play an unexpected role in fine-tuning the brain's neural circuits, according to research published in Neuron. The immune cells that reside there, known as microglia, not only protect the brain from infection and inflammation, they also help physically sculpt circuits in the developing brain. The new work demonstrates that microglia also direct neurons to modify their own connectivity in response to sensory cues.

"To a large extent, the general architecture and wiring of the brain is accomplished by birth," the author says. "But it really requires this robust feedback from the environment to continue that maturation." As an animal interacts with its surroundings, some neuronal connections are eliminated while others are strengthened, the author explains. It's a process that, in humans, continues for decades after birth, the author says.

"What's really important's that during development, the right neurons connect with one another in the right way. We want to have tight control over how many connections there are and how strong the connections are. So that's actually something that sensory experience is important for."

The authors monitored the connections between neurons, or synapses, in a visual processing circuit in the brains of mice. Young mice need visual input at the right time to develop brain pathways related to vision. But if the mice lack visual input for a critical period, the circuits sprout too many synapses and the mice end up with abnormal connections. The team found that the circuits relied on microglia, which, with the right visual stimuli, signaled nearby neurons to prune some of the synapses.

These changes require vision-dependent transcription of the receptor Fn14 in thalamic relay neurons and the induction of its ligand TWEAK in microglia. Fn14 functions to increase the number of bulbous spine-associated synapses at retinogeniculate connections, likely contributing to the strengthening of the circuit that occurs in response to visual experience.

However, at retinogeniculate connections near TWEAK-expressing microglia, TWEAK signals via Fn14 to restrict the number of bulbous spines on relay neurons, leading to the elimination of a subset of connections. Thus, TWEAK and Fn14 represent an intercellular signaling axis through which microglia shape retinogeniculate connectivity in response to sensory experience.

This impact on neural connectivity represents a new role for microglia in the healthy brain, and could help explain why the cells have been implicated in autism and other neurodevelopmental disorders. "I think this study will be seen as a big breakthrough in our mechanistic understanding of how sensory experience and microglia coordinate the process of synaptic pruning that is critical for brain maturation in early life," the senior author says.

https://www.cell.com/neuron/fulltext/S0896-6273(20)30609-7