Researchers have discovered a new glial mechanism in synaptic plasticity that links learning and memory

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Tohoku University researchers have shown that Bergmann glial cells, astrocyte-like cells in the cerebellum, “eat” their neighboring neuronal elements within healthy living brain tissue.

Synapses – structures that allow neurons to pass signals to one another – are regularly pruned throughout a brain’s development to improve its efficiency. Disruption of this is thought to lead to various brain disorders.

The researchers’ findings, which were detailed in the journal Nature Neuroscience, discovered that Bergmann glial engulfing of synapses was enhanced during motor learning in mice’s cerebellum, an important brain region for learning.

Moreover, pharmacological blocking this engulfment inhibited synaptic structural changes, resulting in part of the learning and memory process being lost.

Glial cells, non-neuronal cells occupying about half of the brain, were previously believed to be like glue – merely filling the gap between neurons. However, recent findings show that glia encode information in their own unique way.

“Glia are, of course, not another subcategory of neurons,” says Professor Ko Matsui of Tohoku University’s Super-network Brain Physiology lab, who led the research. “We have yet to uncover the glial impact on information processing.”

Glial cells eating synapses may enhance learning and memory
A represents a 3D electron microscopy analysis of glial phagocytosis. In the brain, presynaptic bouton (blue) sends information to the postsynaptic spine (yellow). Such synaptic contact is surrounded by the glia (magenta). With learning and memory, part of the spine is eaten by the glia (phagocytosis). B shows a 3D reconstruction of the postsynaptic spine. The protrusion (orange) is the part being eaten by the surrounding glia. The reduction in the spine volume leads to efficient motor control. Credit: Morizawa & Matsui

When cells engulf neighboring cells to flush out debris and pathogens, it is called phagocytosis. Phagocytosis by microglia, immune cells in the brain, in damaged and diseased brain tissue has long been recognized. Recent reports have established that astrocytes and microglia phagocytose neuronal elements, including synapses during early brain development or when dramatic neuronal network remodeling occurs in the diseased brain.

Tracing engulfed materials is challenging in healthy brains, since the lysosomes in the glia quickly degenerate the proteins.

Matsui and his team turned to the degeneration-resistant fluorescent protein pHRed to alleviate this problem. Using high-resolution 3D electron microscopy, they captured the Bergmann glia nibbling on synapses parts and other neuronal parts in adult healthy mice brains.

Furthermore, glial phagocytosis was enhanced in brain tissues taken after cerebellar-dependent motor learning tasks. When phagocytosis was pharmacologically blocked, some of the learning was lost.

“Our finding provides a novel glial mechanism in synaptic plasticity linking learning and memory. It is possible that the phagocytic capacity of glia might be variable under the certain states of our mind and glia may play a pivotal role in meta-plasticity of memory formation,” said Matsui.

Lead study investigator Dr. Yosuke Morizawa says that their discoveries could have possible implications for explaining why synaptic shrinkage and loss occur in depression, schizophrenia, and Alzheimer’s disease.

The team’s next step is to see if glial phagocytosis of synapses malfunctions in animal models of these diseases. “A therapeutic strategy designed to target glial phagocytosis might enhance memory and treat certain brain disorders,” added Matsui.


Normal executive function, including learning and memory, is mediated by acute and long-term dynamic regulation of neuronal connectivity. In particular, the hippocampus is actively involved in memory acquisition, formation, and maintenance [1,2,3,4,5,6], with adult neurogenesis and dendritic spine density in this region being particularly important in these functions [7, 8]. However, the focus on mechanisms coordinating cognition has, until recently, been almost exclusively on neurons. Evidence now suggests that microglia may be an important, if under-appreciated, player in these processes.

Microglial cells are a major immune cell population in the brain that coordinate synaptic pruning during development and central responses to pathogens and brain injury in the mature animal [9,10,11,12,13]. It is clear that appropriate synaptic pruning and clearance of excess neurons by microglia during early development is important for the maturation of neural circuits, for instance, with microglial knockout mice displaying immature excitatory synapse functioning [14,15,16]. On the other hand, the role of microglia in learning and memory in the mature animal is less clear.

In the normal adult brain, microglia play a key role in neurogenesis by phagocytosing apoptotic cells [17], controlling the increased neurogenesis caused by environmental enrichment [18], and decreasing neurogenesis following inflammatory challenges [19]. However, a recent surprising finding is that mice perform better on the Barnes maze task for spatial learning and memory in the near complete absence of these cells [20].

In our own work, we have shown that rats that do not effectively reduce microglial number and density in response to a learning task (the radial arm maze) have poorer performance in that task than controls [21]. Learning and memory can also be impaired in mild, and, of course, major neuroinflammation when these cells are at their most active [8, 22]. Conversely, short-term microglial depletion in adult CX3CR1CreER mice can impair motor learning in a rotarod task, stimulate a reduction in synapse formation in motor learning-induced remodeling, and reduce recognition memory in a novel object recognition (NOR) task [23]. Thus, while microglia are necessary for many important functions in the mature animal, including effective responses to pathogens and injury [15, 24], they may play a more nuanced modulatory role in cognitive performance and may curtail or contribute to effective learning under specific conditions.

In this study, we hypothesized that acute and prolonged conditional microglial ablation in a rat model would lead to improvements in learning and memory and that this would be associated with changes in synaptic pruning and neuronal maturation. We used a transgenic rat with the diphtheria toxin receptor (Dtr) inserted into the promoter region of the fractalkine receptor, Cx3cr1, expressed on microglia and monocytes, to allow temporary ablation of microglia upon application of diphtheria toxin (DT). We have previously established that microglial ablation in this model does not induce sickness or an increase in peripheral or central cytokines [22]. We examined performance in several behavioral tasks of learning and memory, and their neurobiological correlates in the hippocampus after microglial ablation and repopulation. We demonstrate that microglial ablation does not affect memory, but memory is improved as these cells repopulate; an effect that may be linked to changes in astrocyte density.

reference link : https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-1729-4#Sec1


More information: Yosuke M. Morizawa et al, Synaptic pruning through glial synapse engulfment upon motor learning, Nature Neuroscience (2022). DOI: 10.1038/s41593-022-01184-5

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