Microglia are the main immune cells of the central nervous system and contribute to both inflammatory damage and tissue repair in neurological diseases. In addition, emerging evidence highlights the role of homeostatic microglia in regulating neuronal activity, interacting with synapses, regulating neural circuits, and regulating behavior.
Recently, the Department of Neurology of the Mayo Clinic in the United StatesWu LongjunThe professor and others are intrends in neurosciencesThis article summarizes how microglia sense and regulate neuronal activity through synaptic interactions, and thus directly participate in neural networks and behaviors. It is proposed that the spatial heterogeneity of microglia-neuron interactions is fundamental to understanding the different functions of microglia in neural circuits and behaviors.
Microglia interact with neurons in the adult brain
1.1 Dynamic interaction with neurons
Microglia have highly motile properties to monitor the central nervous system. In a healthy brain, homeostatic microglia physically interact with various neuronal compartments, such as neuronal cell bodies, axon initiation segments, Langfei's nodes, and synapses, to shape neural structures and regulate neuronal activity.
Neurons form complex circuits that carry information through specific synaptic connections. In the context of brain development, microglia are involved in the formation of circuit structures by participating in synaptic pruning and promoting synaptogenesis. Recent studies have shown that:Microglia can interact with synapses and are therefore an integral part of adult neural networks and various behaviors.
1.2 Sensing and modulating neuronal activity through synaptic interactions
Microglia play a vital role in sensing and regulating neuronal activity. When neuronal activity increases, microglia interact with processes in active neurons are enhanced. These interactions are characterized by process elongation, process convergence, process pouches, and faster movement speeds, resulting in increased contact time that can restore neurons from excitotoxicity. Conversely, when neurons are low in activity (as in the anesthetic state) microglia prolong their processes and increase their kinetics.
In general,A large body of evidence suggests a dynamic interaction between microglia and neuronal activity, highlighting the U-shaped perception pattern of microglia on neuronal activity. Although microglia respond to high and low neuronal activity have different mechanisms, in general, microglia are able to maintain brain homeostasis, achieving a balance of neural activity by interacting with neuronal dynamic processes [fig.].1]。
Microglia regulate and remodel neural circuits in the adult brain
2.1 Synaptic plasticity
Neuronal circuits in the adult central nervous system undergo substantial regulation and remodeling, and synaptic plasticity plays an important role in the formation of neural connections. Several studies have shown that:Microglia-derived factors are involved in the regulation of functional and structural synaptic plasticity. For example, homeostatic microglia can release soluble factors to modulate synaptic plasticity, including brain-derived neurotrophic factor (BDNF), tumor necrosis factor (TNF), and platelet-derived growth factor B (PDGFB). BDNF signaling from microglia has been implicated in facilitating learning-related synapse formation, increased synaptic transmission, and long-term enhancement (LTP) [Fig.].2a]。
Physical interactions between microglia and neurons are another mechanism of synaptic junction regulation. Microglial elongation is in brief contact with the presynaptic and postsynaptic spines, resulting in spine enlargement during contact. This frequency of exposure depends on neuronal activity. Increased neuronal activity or LTP promotes microglial extension of contact with active dendritic spines. Active dendritic spines exhibit longer duration of contact compared to inactive dendritic spines. In addition, these are connectedTactility is associated with an immediate enhancement of synaptic activity and local cortical network synchronization, as well as a decrease in the stability of the hippocampal dendritic spines[fig.2b,c]
In addition to synaptic function, microglia are involved in structural aspects of synaptic plasticity through ECM remodeling. Gene knockout of neuronal interleukin-33 (IL-33) or microglial IL-33 receptor reduced microglial phagocytosis of ECM components and impaired dendritic spine formation and functional plasticity in mice [Fig.].2d]。
2.2 Adult neurogenesis
Adult neurogenesis (also called adult neurogenesis) occurs in the subventricular region (SVZ) of the lateral ventricles and the subgranular region (SGZ) of the dentate gyrus of the hippocampus. Adult neurogenesis is dynamically regulated by various stimuli, such as physical activity, environmental enrichment, and seizures. These newly generated neurons can integrate into circuits and influence behavior.
In a healthy brain, microglia play a key role in promoting beneficial adult neurogenesis and clearing excess adult neurons. For example, in the early stages of adult neurogenesis, a significant proportion of nascent cells undergo apoptosis. Steady-state microglia in adult mouse SGZ are actively involved in the clearance of these apoptotic neonatal cells through cytocytosis, suggesting that adult neoneurons are regulated by multifaceted microglia [Fig.].2e]。Microglia also regulate synapses in adult neurons. Another study also showed that OB and hippocampal microglia were able to form synapses on adult neurons based on the presence of phosphatidylserine [Fig.].2f]。These studies highlight the role of microglia in the formation, pruning, and maintenance of synapses in nascent neurons during adult neurogenesis.
Different microglial functions in neuronal circuits
Microglial manipulation results in region-specific neuronal responses, highlighting the role of microglial spatial heterogeneity in local neural network regulation. For example, microglial depletion has been shown to increase synaptic transmission in the cortex while decreasing synaptic transmission in CEA. In addition, it was found that microglia in SVZ form a functionally distinct class that supports and directs neuronal integration into olfactory circuits.
The spatial heterogeneity of microglia may contribute to region-specific neuronal regulation. Somatic and single-cell analysis of mouse central nervous system tissues reveals specific subtypes of microglia that vary in a time- and region-dependent manner. Regional neuronal diversity appears to play a role in establishing and maintaining region-specific phenotypes of microglia. Even within specific areas of the cortex, microglial states have been shown to be influenced by pyramidal neurons in layer-specific manner.
In addition,The response of microglia is influenced by the microenvironment within local neural circuits. Neurotransmitters are not only released into the synaptic cleft, but can also diffuse in the extracellular space, where they may be perceived by microglia. Microglia have been reported to express a variety of neurotransmitter receptors, such as ionic metabotropic glutamate receptors, gabab receptors, 2-adrenergic receptors, 5-HT2B receptors, and 7-nicotinic acetylcholine receptors. However, the mode of action of these receptors in adult homeostatic microglia warrants further investigation.
Using methods such as microglial ablation and microglial conditioned gene knockout, animal model studies have shown that microglia are able to modulate learning and memory, sleep, anxiety-like behaviors, compulsive behaviors, and alcohol intake [fig.].3]。Mechanically,Microglia THIK-1 K+ channel, CX3CR1, and P2Y12 play an important role in regulating microglia-neuronal circuit interactions.
Summary
In a healthy brain, microglia are characterized by their constant movement of dynamic processes. Differences in microglia monitoring function and how microglia interact with neurons in different brain regions will be important areas of future research. For example, a comparison of cortical microglia with cerebellar microglia showed that microglia exhibited less monitoring capabilities. More research is needed to understand region-specific monitoring of microglia and their role in neural circuitry and behavior. Two-photon imaging of microglia has limitations in imaging depth. In the absence of highly invasive procedures, achieving in vivo imaging of microglia in the subcortical region remains challenging. Recent studies have explored three-photon microscopy for microglial imaging. This emerging imaging technique holds promise for non-invasive imaging of microglia and bringing about 1Visualization of microglia in 1 mm white matter. In addition, real-time imaging of microglia in neuronal circuits in various behavioral contexts is important for future research.
In addition to microglia-synaptic interactions, microglia are in contact with different neuronal compartments, including the cell body of Langfei's node, axon initiation segments, and nodes. Current understanding of how these interactions affect neuronal function in the homeostatic brain is still limited.