Abstract
The C3a receptor (C3aR) is a seven trans-membrane domain G-protein coupled receptor with a range of immune modulatory functions. C3aR is activated by the third complement component (C3) activation derived peptide C3a and a neuropeptide TLQP-21. In the central nervous system (CNS), C3aR is expressed by neural progenitors, neurons as well as glial cells. The non-immune functions of C3aR in the adult CNS include regulation of basal neurogenesis, injury-induced neural plasticity, and modulation of glial cell activation. In the developing brain, C3aR and C3 have been shown to play a role in neural progenitor cell proliferation and neuronal migration with potential implications for autism spectrum disorder, and adult C3aR deficient (C3aR−/−) mice were reported to exhibit subtle deficit in recall memory. Here, we subjected 3 months old male C3aR−/− mice to a battery of behavioral tests and examined their brain morphology. We found that the C3aR−/− mice exhibit a short-term memory deficit and increased locomotor activity, but do not show any signs of autistic behavior as assessed by self-grooming behavior. We also found regional differences between the C3aR−/− and wild-type (WT) mice in the morphology of motor and somatosensory cortex, as well as amygdala and hippocampus. In summary, constitutive absence of C3aR signaling in mice leads to neurodevelopmental abnormalities that persist into adulthood and are associated with locomotive hyperactivity and altered cognitive functions.
Highlights
The complement system is a powerful effector of the innate immune system
C3a receptor (C3aR) is activated by C3a, a 9 kDa fragment generated by the proteolytic cleavage of the third complement component (C3) [3], and a vascular growth factor-derived neuropeptide TLQP-21 [4]
We found that the C3aR−/− mice moved at higher speed (p < 0.01; Figure 1A), and spent more time in motion (p < 0.01; Figure 1B)
Summary
The complement system is a powerful effector of the innate immune system. C3aR is a seven trans-membrane domain G-protein coupled receptor expressed on myeloid cells as well as several types of non-myeloid cell types [1] and exerts a range of both pro-inflammatory and antiinflammatory functions [2]. The non-immune functions of C3aR in the adult CNS include regulation of basal and ischemia-induced neurogenesis [5, 14], synaptic strength and dendritic complexity [15], neuroprotection [16], injury-induced neural plasticity [17], and modulation of glial cell activation [13, 18]; reviewed in [19]. Disturbed complement activity disrupts migration of pyramidal neurons from the ventricular zone to their correct laminar position in the cortical plate, leading to disordered layering of the developing cortex. This developmental defect can be rescued by pharmacological activation of C3aR [21]. Adult C3aR−/− mice were reported to exhibit subtle deficit in recall memory [6], but a detailed analysis of their behavior and brain morphology has been lacking
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