Proper regulation of synaptic density during brain development is necessary for normal brain function, a process that requires a precise balance between synapse formation and elimination.
During brain development, an excess of synapses is first produced, which are selectively removed as the adult brain shapes mature loops. Moreover, abnormal synapses formation and elimination processes are related to the pathological mechanisms of various nervous system diseases.
The complement cascade of the innate immune system plays an important regulatory role in brain development and synaptic elimination in neurological diseases. The activity of C1q leads to the deposition of C3 in synapses, which in turn affects CR3 on microglia and the phagocytosis of microglia regulating synapses. The loss of C1qa or C3 also attenuated symptoms in mice with a variety of neurological disease models, including Alzheimer's disease, frontotemporal lobe dementia, neuropathic pain, and viral-induced memory impairment, and mutations in the C4 gene in humans also had the risk of schizophrenia.
These studies illustrate that complement system abnormalities play an important role in the loss of touch in pathological conditions. In the peripheral immune system, the complement system is tightly controlled by a variety of complement inhibitors to prevent uncontrolled complement activation and damage to its own tissues. However, whether the brain expresses endogenous complement inhibitors, which in turn protect synapses from complement-mediated synapse elimination, is unclear.
In this Nature Neuroscience article, the authors provide evidence that SRPX2 acts as a complement inhibitor to protect complement-mediated synaptic elimination. The authors first discovered that SRPX2 can bind directly to C1q, inhibiting complement pathway activation. In SRPX2−/Y mice, activation of complement and small gel increased. In the dorsal lateral geniculate nucleus (dLGN) of SRPX2−/Y mice, the authors observed a decrease in the number of retinal-knee synapses, while the distinction between gum-phagocytic synapses and RGC axons increased (Fig.1-2).
Fig.1 SRPX2 knockout reduces the number of functional inputs of dLGN neurons
Fig.2 SRPX2 regulates complement-mediated RGC axonal separation in dLGN
C3−/− rats have completely opposite phenotypes and are in C3−/−; In SRPX2−/Y double knockout rats, the C3−/− phenotype was more pronounced, which also shows that in synapses, a complete complement system requires the participation of SRPX2. In the somatosensory cortex (SS) of SRPX2−/Y mice, there is a decrease in synapses in the thalamus cortex, although the cortex and inhibitory synapses are not affected. The authors found that the decrease in synaptic density in the thalamus corticosteroid is due to increased synaptic elimination in the SS cortex, which is visible at C3−/−; Blocked or reversed in SRPX2−/Y mice. Suggests the role of sushi domain proteins in regulating complement-mediated synaptic elimination in the central nervous system.
SRPX2 regulates complement-mediated synaptic elimination in the SS cortex
This work provides a molecular mechanism for temporal and spatial control of complement activity in the brain that limits complement-mediated synaptic elimination to specific synaptic populations and specific time periods during brain development. Taken together, these results suggest that SRPX2 protects synapses in the thalamus and cortex, preventing their elimination by complement mediation.
Article information:
Cong, Q., Soteros, B.M., Wollet, M. et al. The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development. Nat Neurosci 23, 1067–1078 (2020). https://doi.org/10.1038/s41593-020-0672-0
Compiled by Sheena (brainnews creative team)
Reviewer: Simon (Brainnews Editorial Board)