Mechanisms of synaptic pruning exposed: microglia as hunters or gatherers of brain synapses
A recent Perspective in Nature Neuroscience challenges the status quo that the brain´s resident immune cells, called microglia, are responsible for selectively eliminating the contacts between neurons that control memory and learning.
A team from ACHUCARRO and Third Rock Ventures (USA) has tackled the mechanisms underlying a controversial but critical process for the brain´s function through which the contacts between neurons are strengthened or debilitated, called synaptic pruning.
Synapses are neuron-to-neuron contacts used to transmit information across the brain. These plastic structures can change in shape, size, and number depending on the information they encode, and determine the brain´s ability to learn and forget. In the last decade, multiple pieces of evidences showed that microglia, the brain´s immune cells, engulfed synaptic material, suggesting the attractive idea that microglia controlled brain connectivity.
However, this process has never been observed in real time, likely because of technical challenges related to its expected short duration. “The term microglial pruning conveys the idea that microglia actively select which synapses are removed, although live imaging has failed to provide direct evidence of this process”, says the corresponding author Amanda Sierra.
In this Perspective, the authors address this controversy by proposing a new conceptual framework to understand the role of microglial in synaptic pruning. In the first scenario, called culling, microglia act as synapse hunters that select, cleave, and degrade unwanted synapses. In the second one, called scavenging, neurons decide which synapses are to be removed and shed them off, followed by microglial engulfment and degradation.
The therapeutic implications of culling and scavenging are very different: blocking the activity of microglia may be useful if they are responsible for excessive synapse elimination, but detrimental if they are necessary for removing synaptic debris. First author Marta Pereira-Iglesias states that “Discriminating between microglial culling and scavenging is essential to design therapeutic approaches in pathological states in which brain connectivity is altered and a pathological role of microglia is suspected, from autism and schizophrenia to Alzheimer´s and epilepsy”.
“Another aspect of synapse removal that remains poorly studied is the molecular mechanisms governing membrane deformation and scission, as the neuron’s plasma membrane poses a barrier to complete engulfment” says co-author Alejandro Melero, an expert in membrane biophysics.
Finally, the authors recommended approaches to assess the role of microglia in synapse elimination and “encourage researchers to consider that microglial mediated synapse culling is not a universal mechanism of synapse remodeling across ages, brain regions and pathologies”, states co-author Richard Ransohoff.
Read the whole article here:
- Pereira-Iglesias et al. Perspective: Microglia as hunters or gatherers of brain synapses. Nature Neuroscience, 2024, DOI 10.1038/s41593-024-01818-w.