The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease

Stephan, Alexander; Barres, Ben A.; Stevens, Beth

doi:10.1146/annurev-neuro-061010-113810

Cited by 919 publications

(837 citation statements)

References 148 publications

(175 reference statements)

Supporting

Mentioning

780

Contrasting

Unclassified

Order By: Relevance

“…Microglia, the resident immune cells of the brain, are known to alter their morphology in response to damage (31,32). A known function of microglia is to clear neuronal debris by phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

Bocarsly

Fasolino

Kane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

206

151

View full text Add to dashboard Cite

Obesity is a major public health problem affecting overall physical and emotional well-being. Despite compelling data suggesting an association between obesity and cognitive dysfunction, this phenomenon has received relatively little attention. Neuroimaging studies in obese humans report reduced size of brain regions involved in cognition, but few studies have investigated the cellular processes underlying cognitive decline in obesity or the influence of obesity on cognition in the absence of obesity-related illnesses. Here, a rat model of diet-induced obesity was used to explore changes in brain regions important for cognition. Obese rats showed deficits on cognitive tasks requiring the prefrontal and perirhinal cortex. Cognitive deficits were accompanied by decreased dendritic spine density and synaptic marker expression in both brain regions. Microglial morphology was also changed in the prefrontal cortex. Detrimental changes in the prefrontal cortex and perirhinal cortex occurred before metabolic syndrome or diabetes, suggesting that these brain regions may be particularly vulnerable to early stage obesity.O besity is a growing public health concern, affecting more than one-third of the United States adult population (1). Obesity increases the incidence of diabetes, vascular disease, and mental illness, all of which reduce quality of life and place a heavy financial burden on patients and society. Less recognized consequences of obesity are its deleterious effects on cognitive function. Individual cognitive performance, both rudimentary and scholastic, declines with increases in body mass and energy consumption (2-5). These deficits can be observed throughout life, from childhood to late adulthood. Obesity is also associated with an increased incidence of mild cognitive impairment and dementia in the elderly (6).Some evidence suggests that obese individuals have decreased overall brain volume (7), with further studies indicating more specific reductions in the volume of brain regions important for cognition, including the hippocampus, prefrontal cortex (PFC), and anterior cingulate (5,8,9). Few studies, however, have investigated the cellular and biochemical mechanisms that might underlie obesityinduced changes in brain volume and cognitive function.Although clinical studies strongly suggest that obesity produces cognitive impairment and brain atrophy, it is difficult to determine whether these changes arise from obesity itself or from conditions often associated with obesity, like metabolic syndrome, diabetes, and vascular disease. Such conditions, even in the absence of obesity, have been linked to cognitive dysfunction and decreases in brain volume (10-13). Little research has been done exploring the effects of obesity on brain structure and cognition in obese, but otherwise healthy, individuals. To investigate whether obesity in the absence of obvious illness alters brain structure and function, we used a rat model of dietinduced obesity to assess the PFC, the perirhinal cortex (PRC), and the hippocampus...

show abstract

Section: Discussionmentioning

confidence: 99%

“…A known function of microglia is to clear neuronal debris by phagocytosis. Developmental studies indicate that microglia actively prune synapses in the brain (32)(33)(34), raising the possibility that such a process may be occurring in areas of synapse loss with obesity. The link between microglia and synapse loss in obesity is unknown.…”

Section: Discussionmentioning

confidence: 99%

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

Bocarsly

Fasolino

Kane

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

206

151

View full text Add to dashboard Cite

show abstract

“…C1q is the initiating protein complex of the classic complement cascade. Besides its immune functions, C1q has recently been shown to play an essential role in synaptic pruning during embryonic and postnatal CNS development (44)(45)(46). We therefore interrogated the expression of C1q protein by immunostaining.…”

Section: Sma Primarily Affects Spinal Cord Mnsmentioning

confidence: 99%

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhang

Pinto

Wan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

161

140

View full text Add to dashboard Cite

The motor neuron (MN) degenerative disease, spinal muscular atrophy (SMA) is caused by deficiency of SMN (survival motor neuron), a ubiquitous and indispensable protein essential for biogenesis of snRNPs, key components of pre-mRNA processing. However, SMA's hallmark MN pathology, including neuromuscular junction (NMJ) disruption and sensory-motor circuitry impairment, remains unexplained. Toward this end, we used deep RNA sequencing (RNA-seq) to determine if there are any transcriptome changes in MNs and surrounding spinal cord glial cells (white matter, WM) microdissected from SMN-deficient SMA mouse model at presymptomatic postnatal day 1 (P1), before detectable MN pathology (P4-P5). The RNA-seq results, previously unavailable for SMA at any stage, revealed cell-specific selective mRNA dysregulations (∼300 of 11,000 expressed genes in each, MN and WM), many of which are known to impair neurons. Remarkably, these dysregulations include complete skipping of agrin's Z exons, critical for NMJ maintenance, strong upregulation of synapse pruning-promoting complement factor C1q, and down-regulation of Etv1/ER81, a transcription factor required for establishing sensory-motor circuitry. We propose that dysregulation of such specific MN synaptogenesis genes, compounded by many additional transcriptome abnormalities in MNs and WM, link SMN deficiency to SMA's signature pathology.transcriptome perturbations | Z+ (neuronal) agrin | C1q complex S pinal muscular atrophy (SMA) is an autosomal recessive motor neuron (MN) degenerative disease and a leading genetic cause of infant mortality (1, 2). SMA is caused by deletions or point mutations in the survival of motor neurons 1 gene (SMN1) (3), exposing a splicing defect in a duplicated gene (SMN2), which produces predominantly exon 7-skipped mRNA (SMNΔ7) (4). This in turn creates a degron that destabilizes the SMNΔ7 protein, resulting in reduced SMN levels (SMN deficiency) (5). SMA pathology has been extensively characterized in patients as well as a widely used SMA mouse model (6). Major morphological and biochemical deficits have been found at neuromuscular junctions (NMJs) and sensory-motor synapses. NMJ defects are first detectable at postnatal day 5 (P5), including presynaptic defects of terminal arborization and intermediate neurofilament aggregation in MNs, poor postsynaptic organization of AChRs in muscle, as well as reduced synaptic vesicle density and release at the NMJ (7-9). Importantly, similar NMJ defects have been reported in type I (the most severe type) SMA human fetuses (10). SMA MNs have also been shown to be hyperexcitable and loss of proprioceptive synapses on the somata, and proximal dendrites of SMA MNs (MN deafferentation) occurs no later than P4 (11-13). These findings indicate that both peripheral (NMJs) and central (sensory-motor) synapses are affected in SMA mice at early stage of disease. Although SMA is clinically manifested primarily in MNs, recent studies have shown that other cell types and nonneuronal tissues are also involved (13,14,15). SMN,...

show abstract

“…9 Among the processes induced by the non-classical functions of the C1q molecule, we find: the modulation of various immune cells, 10 the regulation of cell migration (chemotaxis), adhesion, survival and differentiation, 11 coagulation, 12 angiogenesis 13 and embryonic development, including neurological synapse function. 14 There is mounting evidence to support the idea that C1q and its receptors are also involved in the regulation of cancer. The recently postulated ability of C1q to induce apoptosis in prostate cancer cells by coordinating signal transduction pathways linked to the tumor suppressor WW domain containing oxidoreductase (WWOX), 15 has highlighted its important role as a humoral factor which is needed to directly block cancer cell proliferation, without the involvement of antitumor antibodies and the consequent activation of the classical complement pathway.…”

Section: Introductionmentioning

confidence: 99%

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

et al. 2016

View full text Add to dashboard Cite

There is an ever increasing amount of evidence to support the hypothesis that complement C1q, the first component of the classical complement pathway, is involved in the regulation of cancer growth, in addition to its role in fighting infections. It has been demonstrated that C1q is expressed in the microenvironment of various types of human tumors, including breast adenocarcinomas. This study compares carcinogenesis progression in C1q deficient (neuT-C1KO) and C1q competent neuT mice in order to investigate the role of C1q in mammary carcinogenesis. Significantly accelerated autochthonous neu C carcinoma progression was paralleled by accelerated spontaneous lung metastases occurrence in C1q deficient mice. Surprisingly, this effect was not caused by differences in the tumor-infiltrating cells or in the activation of the complement classical pathway, since neuT-C1KO mice did not display a reduction in C3 fragment deposition at the tumor site. By contrast, a significant higher number of intratumor blood vessels and a decrease in the activation of the tumor suppressor WW domain containing oxidoreductase (WWOX) were observed in tumors from neuT-C1KO as compare with neuT mice. In parallel, an increase in Her2/neu expression was observed on the membrane of tumor cells. Taken together, our findings suggest that C1q plays a direct role both on halting tumor angiogenesis and on inducing apoptosis in mammary cancer cells by coordinating the signal transduction pathways linked to WWOX and, furthermore, highlight the role of C1q in mammary tumor immune surveillance regardless of complement system activation.Abbreviations: BALB-C1KO, BALB/c mice deficient for the C1qA; BALB-C3KO, BALB/c mice deficient for C3; C1KO, C1q deficient; C1qR, C1q receptor; CR3, complement receptor 3; EMT, epithelial-to-mesenchymal transition; KLRK1 or NKG2D, killer cell lectin-like receptor subfamily K, member 1; MDCS, myeloid-derived suppressor cells; neuT, rat Her2/neu transgenic; neuT-BKO mice, neuT mice deficient in antibody production; neuT-C1KO mice, neuT mice deficient for the C1qA molecule; neuT-C3KO mice, neuT mice deficient for the C3 molecule; NK, natural killer; pWWOX, phospho WWOX; Treg, T regulatory; WWOX, WW domain containing oxidoreductase

show abstract

The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease

Cited by 919 publications

References 148 publications

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function

Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

The non-inflammatory role of C1q during Her2/neu-driven mammary carcinogenesis

Contact Info

Product

Resources

About