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Click the blue word to pay attention to the synapse pruning mediated by microglia during our developmental period, which can effectively remove some redundant synapses and ensure the correct neural connection.
However, abnormal behaviors such as autism, schizophrenia and other diseases appear in adulthood after pruning abnormalities during this period.
In addition, abnormal synaptic pruning occurs in adulthood, such as Alzheimer's disease.
In the peripheral immune system, phagocytes rely on immune molecules to identify pathogens or cell debris that need to be cleaned up.
In the central nervous system, there is also such a class of immune molecules: the complement system C3 and C1q, which serve as the "eat me" signaling pathway to help microglia quickly find weak synapses that need to be cleared.
In addition, smart brains won’t let these “eat me” signals do whatever they want, so “Don’t eat me” signals are needed to counterbalance the “eat me” signals to ensure that the microglia can be stable and orderly.
, Clean up synapses scientifically, instead of wantonly indulging the phagocytic function of microglia.
One of the known "Don't eat me'" signals is the CD47-SIRPα signal.
CD47 belongs to the immunoglobulin superfamily, and its ligands include SIRPα, thrombospondin-1 (TSP-1) and integrin.
SIRPα is a transmembrane protein whose extracellular region contains three immunoglobulin superfamily-like regions.
On April 2, 2021, the research team of Professor Li Liang and Zeng Ke from the School of Life Sciences of Nanjing University found in the journal Nature Communications that after the lack of SIRPα in the developmental stage, the phagocytic synapse of microglia increased, which caused a decrease in synaptic density.
One effect also appears in AD disease.
The researchers found that SIRPα is mainly expressed on microglia and neurons, with a small amount expressed on astrocytes.
The expression of SIRPα on microglia is time-dependent, it is highly expressed on the 5th day after birth, the expression begins to decline 1 month after birth, and the expression level is low after adulthood.
Therefore, after crossing Cx3cr1-CreERT2 with SIRPα-fl/fl mice, they fed tamoxifen after birth to achieve specific knockout of SIRPα on microglia in the early developmental stage, hereinafter referred to as SIRPα-cKO mice.
Specific knock-out of microglial SIRPα synaptic pruning enhances synaptic density in the primary visual cortex of SIRPα-cKO mice on the 30th day after birth, while the synaptic density in the hippocampal CA1 area begins to decrease from the 15th day after birth.
And the excitatory postsynaptic current is weakened.
Through the three-dimensional reconstruction of microglia, it was found that the proportion of phagocytic synapses in the visual cortex of SIRPα-cKO mice was significantly increased, which indicates that the reduction of visual cortex synapses may be caused by the excessive phagocytosis of synapses by microglia .
In addition, the density of synapses in the hippocampus was also reduced after CD47 was knocked out, and the proportion of synapses phagocytosed by microglia also increased.
CD47 is widely expressed on synapses in vitro and in vivo experiments.
It is found that CD47 is expressed on synapses.
After tetrodotoxin (TTX) inhibits neuronal activity or chronically inhibits neurons through chemical genetics, CD47 protein expression decreases.
The number of CD47-positive synapses is also decreasing.
In addition, the number of CD47-positive synapses in SIRPα-cKO mice increased, indicating that synapses that did not express CD47 were more likely to be phagocytosed by microglia.
Previous studies have shown that microglia prefer synapses with weak phagocytic activity.
Therefore, when neuronal activity decreases, the expression of CD47 decreases.
These synapses are more likely to be phagocytosed after losing the protection of CD47.
In Alzheimer's disease (AD), there is early synapse loss, and microglia-mediated synaptic pruning regulates this early loss.
Researchers found that the expression of SIRPα protein in the cortex of AD patients was significantly reduced.
In AD model mice, the expression of SIRPα in microglia began to decrease at 5 months of age, which was earlier than the formation of amyloid plaques.
Researchers crossed AD model mice with SIRPα-cKO mice and found that the specific reduction of SIRPα on microglia did not affect the formation of amyloid plaques, but it would aggravate the loss of synapses.
Subsequent experiments found that the increased synapse loss was caused by microglia phagocytosing too many synapses.
This indicates that the down-regulation of SIRPα expression may be involved in the abnormal synaptic loss in AD disease.
In summary, this paper reveals that during the process of CD47-SIRPα signal negatively regulate synaptic pruning, the down-regulation of SIRPα expression in AD disease promotes microglia to phagocytose excessive synapses, causing cognitive behavioral disorders.
The "Don't eat me'" signal serves as a signal that protects the synapse.
In the case of weak nerve activity, this protective effect will be weakened, as is the case in AD disease.
[References] 1.
https://doi.
org/10.
1038/s41467-021-22301-1 The pictures in the article are all from the references
However, abnormal behaviors such as autism, schizophrenia and other diseases appear in adulthood after pruning abnormalities during this period.
In addition, abnormal synaptic pruning occurs in adulthood, such as Alzheimer's disease.
In the peripheral immune system, phagocytes rely on immune molecules to identify pathogens or cell debris that need to be cleaned up.
In the central nervous system, there is also such a class of immune molecules: the complement system C3 and C1q, which serve as the "eat me" signaling pathway to help microglia quickly find weak synapses that need to be cleared.
In addition, smart brains won’t let these “eat me” signals do whatever they want, so “Don’t eat me” signals are needed to counterbalance the “eat me” signals to ensure that the microglia can be stable and orderly.
, Clean up synapses scientifically, instead of wantonly indulging the phagocytic function of microglia.
One of the known "Don't eat me'" signals is the CD47-SIRPα signal.
CD47 belongs to the immunoglobulin superfamily, and its ligands include SIRPα, thrombospondin-1 (TSP-1) and integrin.
SIRPα is a transmembrane protein whose extracellular region contains three immunoglobulin superfamily-like regions.
On April 2, 2021, the research team of Professor Li Liang and Zeng Ke from the School of Life Sciences of Nanjing University found in the journal Nature Communications that after the lack of SIRPα in the developmental stage, the phagocytic synapse of microglia increased, which caused a decrease in synaptic density.
One effect also appears in AD disease.
The researchers found that SIRPα is mainly expressed on microglia and neurons, with a small amount expressed on astrocytes.
The expression of SIRPα on microglia is time-dependent, it is highly expressed on the 5th day after birth, the expression begins to decline 1 month after birth, and the expression level is low after adulthood.
Therefore, after crossing Cx3cr1-CreERT2 with SIRPα-fl/fl mice, they fed tamoxifen after birth to achieve specific knockout of SIRPα on microglia in the early developmental stage, hereinafter referred to as SIRPα-cKO mice.
Specific knock-out of microglial SIRPα synaptic pruning enhances synaptic density in the primary visual cortex of SIRPα-cKO mice on the 30th day after birth, while the synaptic density in the hippocampal CA1 area begins to decrease from the 15th day after birth.
And the excitatory postsynaptic current is weakened.
Through the three-dimensional reconstruction of microglia, it was found that the proportion of phagocytic synapses in the visual cortex of SIRPα-cKO mice was significantly increased, which indicates that the reduction of visual cortex synapses may be caused by the excessive phagocytosis of synapses by microglia .
In addition, the density of synapses in the hippocampus was also reduced after CD47 was knocked out, and the proportion of synapses phagocytosed by microglia also increased.
CD47 is widely expressed on synapses in vitro and in vivo experiments.
It is found that CD47 is expressed on synapses.
After tetrodotoxin (TTX) inhibits neuronal activity or chronically inhibits neurons through chemical genetics, CD47 protein expression decreases.
The number of CD47-positive synapses is also decreasing.
In addition, the number of CD47-positive synapses in SIRPα-cKO mice increased, indicating that synapses that did not express CD47 were more likely to be phagocytosed by microglia.
Previous studies have shown that microglia prefer synapses with weak phagocytic activity.
Therefore, when neuronal activity decreases, the expression of CD47 decreases.
These synapses are more likely to be phagocytosed after losing the protection of CD47.
In Alzheimer's disease (AD), there is early synapse loss, and microglia-mediated synaptic pruning regulates this early loss.
Researchers found that the expression of SIRPα protein in the cortex of AD patients was significantly reduced.
In AD model mice, the expression of SIRPα in microglia began to decrease at 5 months of age, which was earlier than the formation of amyloid plaques.
Researchers crossed AD model mice with SIRPα-cKO mice and found that the specific reduction of SIRPα on microglia did not affect the formation of amyloid plaques, but it would aggravate the loss of synapses.
Subsequent experiments found that the increased synapse loss was caused by microglia phagocytosing too many synapses.
This indicates that the down-regulation of SIRPα expression may be involved in the abnormal synaptic loss in AD disease.
In summary, this paper reveals that during the process of CD47-SIRPα signal negatively regulate synaptic pruning, the down-regulation of SIRPα expression in AD disease promotes microglia to phagocytose excessive synapses, causing cognitive behavioral disorders.
The "Don't eat me'" signal serves as a signal that protects the synapse.
In the case of weak nerve activity, this protective effect will be weakened, as is the case in AD disease.
[References] 1.
https://doi.
org/10.
1038/s41467-021-22301-1 The pictures in the article are all from the references
