Summary: This brief review discusses the complement system's dual role in the brain, highlighting its essential function in innate immunity and its involvement in both beneficial synaptic refinement during development and detrimental synaptic loss in neurodegenerative diseases like Alzheimer's. It specifically mentions C1q and C3 as key components in developmental synaptic pruning and notes that excessive pruning can be harmful in pathological conditions. The review aims to cover the complement system's contribution to neurodegeneration and cognitive deficits, as well as potential therapeutic strategies targeting this system.

Summary: This review focuses on the critical role of microglia in tauopathies, including Alzheimer's disease (AD), highlighting that synapse loss is an early event strongly correlated with cognitive decline. It explains how tau pathology is linked to neuroinflammation and reactive microglia, with AD risk genes like TREM2 and APOE modulating microglial responses. The abstract emphasizes that microglia actively contribute to synaptic dysfunction by abnormally phagocytosing synaptic components and are involved in the synaptic spreading of pathological tau, making them a key target for potential immunotherapies.

Summary: This review examines the dual role of microglia in regulating synaptic plasticity and learning/memory. It highlights how resting microglia, via complement pathways (C1q, C3) and other signaling, prune synapses during normal neurodevelopment, influencing experience-dependent plasticity in areas like the visual cortex and memory formation. The abstract also notes that activated microglia, in response to injury or neuroinflammation, can contribute to synaptic deficits seen in aging, Alzheimer's disease, and other neurological disorders, suggesting therapeutic potential in manipulating microglial function.

Summary: This review discusses synaptic elimination, a process crucial for refining neural connectivity, and highlights the recent discovery of the classical complement cascade's role in this phenomenon. Specifically, it details how microglial cells recognize complement component 3 (C3) bound to synapses, leading to their engulfment. The paper focuses on the potential involvement of excessive synaptic elimination in Alzheimer's disease, citing evidence of dendritic spine loss, increased complement protein association with synapses, and augmented microglia-mediated pruning in animal models. It also briefly touches upon the relevance of this process in other neurological disorders like multiple sclerosis and schizophrenia.

Summary: This paper highlights the recently discovered role of the classical complement cascade in eliminating central nervous system (CNS) synapses. Complement proteins are found at developing synapses during periods of active elimination and are crucial for normal brain wiring, functioning similarly to immune clearance by tagging synapses for removal by microglia expressing complement receptors. The abstract also notes that astrocytes can induce complement component expression. Furthermore, it posits that the early synapse loss seen in neurodegenerative diseases may involve a reactivation of these developmental complement-mediated elimination mechanisms, as complement proteins are upregulated in many CNS diseases before neuron loss.

Summary: This review discusses the emerging direct role of microglia in neurodegeneration observed in Alzheimer's disease (AD) by promoting the phagocytosis of neuronal and synaptic structures. It highlights that while microglia were previously known for neuroinflammation, recent studies show their direct involvement in AD pathogenesis, potentially independent of beta-amyloid peptides. The paper reviews these studies, speculates on cellular mechanisms, regulation by risk genes and sleep, and explores therapeutic targets for microglia-mediated synapse loss.

Summary: This study investigates the terminal complement pathway's role in synaptic loss in Alzheimer's disease (AD) models, aiming to clarify mechanisms beyond C1q and C3 tagging for microglial phagocytosis, particularly the unexplored role of the Membrane Attack Complex (MAC). The research addresses whether complement is activated through to MAC at synapses, if MAC contributes to synaptic loss, and if MAC inhibition can prevent this loss, utilizing novel methods to quantify complement components in brain homogenates and synaptoneurosomes from wild-type and AD model mice.

Summary: This review examines the dynamics of the complement, cytokine, and chemokine systems in regulating synaptic function and dysfunction, particularly in the context of Alzheimer's disease (AD). It highlights that synaptic loss is a key neuropathological hallmark of AD and correlates strongly with cognitive impairment. The abstract notes emerging evidence suggesting that immune system-mediated synaptic pruning may initiate early AD pathogenesis and aims to explore the interplay between neurons, microglia, and astrocytes, along with the roles of complement, MHC-I, and CX3CL1 pathways in synaptic elimination during both development and AD, with a view towards potential therapeutic targets.

Summary: This abstract discusses the pathological hallmarks of Alzheimer's disease (AD), including amyloid plaques and neurofibrillary tangles, which are accompanied by neuroinflammation and synapse loss driven by activated microglia. It highlights the dual role of microglia in AD, either clearing amyloid-beta (Aβ) or exacerbating neuroinflammation and synaptotoxicity. The paper notes that aggregated Aβ activates microglia via toll-like receptor 4 (TLR4) and that complement components are linked to AD pathology, with aggregated Aβ activating complement leading to microglial phagocytosis and synapse loss. It further explains that systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement pathways, contributing to neuroinflammation, Aβ accumulation, synapse loss, and neurodegeneration, suggesting that targeting these signaling pathways could be a therapeutic approach for AD.

Summary: This review examines the role of innate immune cells, primarily microglia, in brain development, contrasting their function during development with their roles later in life. It also covers the impact of early-life disturbances on developing microglia, the influence of biological sex on microglial function, and their potential involvement in developmental brain disorders, while also noting their established role in conditions like Alzheimer's disease and highlighting areas for future research in developmental neuroimmunology.

Summary: This review discusses the critical roles of microglia in brain maturation and neurodevelopmental processes, suggesting that microglial dysfunction may contribute to neurodevelopmental disorders (NDDs). It outlines how microglia mechanistically sculpt the developing brain and neuronal circuits, provides autism spectrum disorder as an example of microglial dysregulation in NDD pathogenesis, and explores the emerging research on how the gut microbiome influences microglial biology and NDD progression.

Summary: This review will broadly introduce studies on the roles of microglia, the brain's resident immune cells, in regulating synaptic plasticity, including synapse formation and elimination. It highlights that over the past 15 years, significant research has elucidated the molecular mechanisms underlying microglia-dependent synaptic regulation, and disruptions in these processes are linked to synaptic dysfunction and brain diseases.

Summary: This study investigates the interaction between astrocytes and microglia in Alzheimer's disease (AD) mouse models, focusing on the complement pathway. It reveals that amyloid-beta (Aβ) activates astrocytic NF-κB, leading to C3 release, which then acts on microglial C3a receptors (C3aR). While acute C3/C3a activation enhances microglial phagocytosis, chronic exposure attenuates it, a effect blocked by C3aR antagonism or genetic deletion. In AD mouse models, increased astroglial NF-κB and C3 worsen amyloid pathology and neuroinflammation, but treatment with a C3aR antagonist ameliorates these effects. The findings highlight a complement-dependent feedback loop where C3 released by astrocytes, acting on both neuronal and microglial C3aR, contributes to AD pathogenesis by altering cognition and impairing microglial phagocytosis, suggesting C3aR inhibition as a therapeutic target.

Summary: This review discusses the multifaceted roles of microglia in the brain, including their involvement in neuronal circuit formation and function. It highlights that during development, microglia participate in pruning mechanisms, while in the mature brain, they influence synaptic signaling, provide trophic support, and shape plasticity. The paper notes regional variations in microglial characteristics that may be linked to the maturation and function of specific neuronal circuits and reviews their roles in the thalamus, hippocampus, cortex, and cerebellum, focusing on in vivo studies and their implications for neurodevelopmental and neuropsychiatric disorders.

Summary: This review examines synapse elimination, a critical process in both normal neurodevelopment and the pathogenesis of neurodegenerative diseases. It highlights recent evidence implicating immune molecules, particularly those from the classical complement cascade, in the elimination of synapses during development. The paper explores the hypothesis that these developmental mechanisms are recapitulated in neurodegenerative conditions, contributing to early synapse loss and dysfunction, and discusses various neuroimmune proteins involved in these processes in both developing and diseased brains.

Summary: This review examines the involvement of complement system components in normal brain development, including processes like neurogenesis, neuronal migration, and synaptic remodeling, as well as their role in neurodevelopmental disorders such as schizophrenia, autism spectrum disorder, and Rett syndrome. It evaluates the evidence linking complement dysfunction to these conditions, considering both inflammation-dependent and -independent mechanisms, and highlights the role of complement mutations in rare disorders like 3MC syndrome, while also discussing the complement system's function after inflammatory insults.

Summary: This review summarizes the role of various glial cells, including microglia, in regulating synaptic dysfunction, which is a hallmark of Alzheimer's disease (AD). It highlights that while glial cells are crucial for normal brain functions like synapse formation and maturation, their overactivation during AD progression contributes to synaptic impairment, neuroinflammation, and cognitive decline, suggesting that glia-synapse communication is a key area for understanding AD mechanisms.

Summary: This review explores the multifaceted roles of microglia in the brain, covering their involvement in synapse formation, circuit sculpting, myelination, plasticity, and cognition across human and mouse development. It examines microglia's functions in both homeostatic conditions and neurodevelopmental disorders, detailing how altered interactions with neurons and oligodendrocytes, changes in cytokine and growth factor activities, and modifications in the complement system contribute to these processes, while also looking towards future research directions.

Summary: This review critically appraises recent literature on how environmental and genetic factors perturb microglial activity during pre- and early post-natal stages, highlighting their critical roles in synaptic maturation and brain wiring. It discusses the potential for defective synaptic circuit maturation due to these perturbations and examines the long-lasting consequences on synaptic function and vulnerability to neurodevelopmental and psychiatric disorders.

Summary: This study investigated the effects of traumatic brain injury (TBI) in aged mice, a population with increased TBI incidence and decreased recovery, and TBI's link to neurodegenerative disorders like Alzheimer's. Using a focal contusion model, researchers observed chronic inflammation characterized by increased microglial activation and phagocytic activity, leading to significant memory deficits 30 days post-injury. They identified increased complement components (C1q, C3, CR3) on synapses, correlating with synapse loss. Crucially, both genetic and pharmacological blockade of the complement pathway ameliorated memory deficits in aged TBI animals, suggesting that targeting the complement cascade is a potential therapeutic strategy for cognitive decline following TBI in the aging population.

Summary: This review examines the critical role of synapse elimination, or synaptic pruning, during brain development, emphasizing the involvement of the complement cascade and microglia. It details how complement proteins opsonize excess synapses, marking them for phagocytosis by microglia expressing complement receptors. The process is modulated by various molecular signals, including complement inhibitors and factors influencing microglial activity. The abstract highlights that dysregulation of these complement-microglia mechanisms is implicated in developmental brain disorders and suggests this system as a potential therapeutic target for such conditions.

Summary: This review highlights the crucial roles of microglia in brain development and functional connectivity, emphasizing their dynamic processes for sensing the environment and responding to stimuli. It details how microglia exert immune functions like cytokine release and phagocytosis, and how their crosstalk with various brain cells contributes to synaptic pruning, neurogenesis, and other vital processes. The review specifically focuses on neuron-derived molecular signals ('find-me,' 'eat-me,' 'don't eat-me') that guide microglial activity in synaptic refinement during development and explores novel ideas for microglial roles in disease, aiming to provide insights for drug discovery and treatment strategies targeting synaptic dysfunction.

Summary: This review article discusses the role of glia, particularly microglia and astrocytes, in regulating synaptic structure and function, emphasizing their pivotal role in synaptic elimination. It highlights that inflammatory challenges during the critical perinatal period of brain development can alter synaptic organization and function, with potential implications for both neurodevelopmental and neurodegenerative disorders.

Summary: This review summarizes the emerging roles of microglia in normal brain development, particularly their involvement in synaptic pruning through innate immune signaling. It highlights that microglia, via receptors like fractalkine, complement, and TREM2, modulate developmental synaptic pruning. The authors' previous work indicates that microglia engulf oligodendrocyte progenitor cells (OPCs) in the corpus callosum during early postnatal development in a fractalkine-dependent manner, which is crucial for establishing the appropriate OPC:axon ratio for myelin ensheathment and proper action potential propagation. The paper discusses the spatial and temporal aspects of microglial elimination of OPCs and synapses, suggesting implications for shaping neuronal function architecture.

Summary: This article reviews the role of the immune system, particularly complement-mediated synaptic pruning during critical periods of early life, in shaping brain development and its connection to psychiatric disorders like schizophrenia and autism spectrum disorders. It highlights the need to understand the complex interactions between the immune system, sex, and developmental trajectories, noting that perturbations in neuroimmune interactions during development can lead to long-term psychiatric consequences, and aims to explore these mechanisms beyond the visual system into areas relevant to psychiatric conditions.

Summary: This review examines the role of complement-mediated phagocytosis in the visual system, covering both normal physiological processes during development and pathological roles in neurodegenerative diseases. It highlights how complement activation products opsonize synaptic material for microglial removal, a process crucial for synapse refinement in the retina and lateral geniculate nucleus during development. The paper also discusses how aberrant phagocytosis, driven by complement, contributes to injury in conditions like multiple sclerosis, stroke, and traumatic brain injury, with specific attention to retinal diseases such as glaucoma and age-related macular degeneration, and explores potential therapeutic strategies involving complement inhibition.

Summary: This review discusses the role of microglia in the maturation of the medial prefrontal cortex (mPFC) circuits during postnatal development, highlighting how microglia influence synaptogenesis and synaptic refinement through molecular pathways and immune signals. It examines how disruptions in these processes are linked to neurodevelopmental and psychiatric disorders like schizophrenia and autism spectrum disorder, suggesting that microglial mechanisms may connect environmental risk factors with genetic programs to aberrantly shape mPFC circuitry.

Summary: This review examines the essential homeostatic roles of microglia during central nervous system development, drawing parallels between these developmental mechanisms and their re-emergence in disease and injury contexts.

Summary: This review examines the role of microglia in early neurodevelopment, particularly in the context of maternal immune activation during gestation, which is linked to neurodevelopmental disorders like schizophrenia and autism spectrum disorder. It highlights how microglia, as resident CNS immune cells, are involved in various prenatal and early postnatal neurodevelopmental processes and how maternal immune activation might interfere with their function, potentially leading to long-term consequences. The review also discusses recent single-cell RNA-sequencing studies on prenatal microglia and proposes that early microglial priming, possibly via epigenetic reprogramming, could be related to neurodevelopmental disorders.

Summary: This review examines the multifaceted roles of microglia in the central nervous system, highlighting their established immunological functions and their emerging importance in neurodevelopmental processes such as neurogenesis and synaptic pruning. It details how microglia interact with neurons and macroglia to support development and refine neural circuits, influenced by trophic support, cytokine signals, and metabolic cues. The abstract also emphasizes the impact of the host microbiome on microglial function, suggesting microglia act as a link between neurodevelopmental disorders like autism and schizophrenia and microbial influences, particularly in models of maternal immune activation.

Summary: This review examines the critical role of microglia in Alzheimer's disease (AD), focusing on neuroinflammatory and phagocytic mechanisms. It highlights the involvement of key molecular targets such as NLRP3, the complement system, and TREM2 in modulating microglial functions within the context of AD pathogenesis. The paper aims to identify potential therapeutic targets and interventions for disease modification in AD.

Summary: This review focuses on the complement system's involvement in Alzheimer's disease (AD) pathogenesis, noting its surprising roles in both normal brain development and pathological remodeling. While the complement system is known to protect against infection, it also drives inflammation and exacerbates pathology in various neurological conditions, including AD. The paper aims to review the current understanding of complement's function in the healthy brain, its influence on AD genesis and progression, and the challenges associated with therapeutic complement inhibition in AD patients.

Summary: This review emphasizes the crucial role of microglia in regulating neuronal viability, synaptic dynamics, and neurodevelopmental outcomes, particularly within the context of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and schizophrenia (SZ). While acknowledging the significant impact of NDDs and the growing attention to their neurobiological basis, the abstract highlights that the specific roles of microglia in ASD and SZ remain unclear. The paper aims to meticulously emphasize the multifaceted roles microglia play during neurodevelopment and to postulate potential microglial mechanisms involved in these conditions, underscoring the need for a comprehensive understanding of microglia-neuron interactions for developing effective therapeutic strategies.

Summary: This review explores the multifaceted roles of the complement system, extending beyond immunity to brain development and pathology. It highlights the complement system's involvement in synaptic pruning, a crucial process for eliminating excess synapses in the developing brain. The abstract indicates the review will cover the complement system's contribution to embryonic and adult neurogenesis, neuronal migration, and developmental synaptic elimination in the normal brain, as well as its role in synapse loss associated with psychiatric disorders like schizophrenia and neurological diseases, evaluating potential therapeutic strategies targeting the complement system.

Summary: This paper reviews the role of microglia in Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by behavioral and social deficits. While acknowledging that microglia are crucial for CNS homeostasis and can promote synaptic pruning during early development, the abstract highlights that many ASD studies have focused on neuronal changes. It proposes that microglial abnormalities may underlie ASD phenotypes and aims to summarize current research on microglia's function and neurodevelopmental impact in ASD, exploring microglia-related pathways as potential therapeutic targets.

Summary: This review examines the contribution of microglia to the pathology of neurodevelopmental disorders in humans, contrasting human and rodent microglia and highlighting differences. It discusses microglial involvement in basic neurodevelopmental processes and their role in the etiology of autism spectrum conditions and schizophrenia. The paper also covers how recent technologies are advancing the understanding of microglia-neurodevelopmental disorder links and reviews promising treatment approaches targeting microglia.

Summary: This review provides an overview of microglia's interactions with neurons in physiological conditions, focusing on their role in modulating synapse fate and function, particularly their neurodevelopmental influence on synapses. It highlights how microglia dysfunction, often linked to neuroinflammation, plays a significant role in the pathogenesis of Autism Spectrum Disorder (ASD), affecting neural function, synapse formation, and the excitatory-inhibitory balance.

Summary: This review explores synaptic pruning, a vital process for refining neural circuits by eliminating unstable connections, regulated by neural activity and experience-dependent mechanisms. It highlights the involvement of molecular signals and "eat me"/"don't eat me" states, noting that glial cells interact with neurons to clear synapses under physiological conditions. The paper also discusses how imbalanced pruning contributes to neurological diseases such as autism, schizophrenia, and Alzheimer's disease. Furthermore, it examines the molecular mechanisms underlying synaptic pruning during neural development and its association with neurological disorders, while also reviewing the application of emerging optical and imaging technologies for observing synaptic structure and function, with potential for clinical translation.

Summary: This study demonstrates that spatially restricted complement activation drives stress-induced microglia activation and synapse loss in the upper layers of the medial prefrontal cortex (mPFC) in male mice. Using single-cell RNA sequencing, a stress-associated microglia state marked by high apolipoprotein E expression was identified in these layers. Mice lacking complement component C3 were protected from stress-induced synapse loss and behavioral deficits, suggesting a critical role for C3 in mediating these effects and highlighting the potential of complement and microglia activation in stress-related disorders.

Summary: This paper reviews the role of microglia and astrocytes at the tripartite synapse during postnatal development, highlighting their involvement in synapse formation, maturation, and elimination, which shapes neural connectivity and synaptic plasticity. It suggests that disruptions in these glial cells during early postnatal development may contribute to synaptic dysfunction underlying neurodevelopmental disorders such as autism spectrum disorder and schizophrenia.