The Dual Role of Microglial Synaptic Pruning in Autism Spectrum Disorder and Schizophrenia: A Literature Review

Abstract

This review investigates the dual roles of microglial synaptic pruning dysfunction in Autism Spectrum Disorder (ASD) and schizophrenia. While ASD is characterized by insufficient synaptic pruning leading to synaptic overabundance, schizophrenia exhibits excessive pruning and synaptic loss. This review aims to synthesize current knowledge on these distinct roles and clarify their associations with divergent behavioral phenotypes, ultimately contributing to identifying new research questions and potential therapeutic targets. Peer-reviewed literature from 2000-2025 was identified and analyzed using open-access databases such as PubMed, Scopus, and Google Scholar. Articles were selected based on relevance to microglial synaptic pruning in mammalian models of ASD and schizophrenia, focusing on synaptic markers, electrophysiological recordings, and complement cascade expression. Exclusion criteria included non-mammalian models, primary focus on other disorders, opinion articles and editorials, and use of purely in vitro evidence. In ASD, findings consistently indicate increased synaptic density and immature dendritic spines, particularly in the prefrontal cortex (PFC), temporal lobe, and cingulate cortex, linked to sensory hypersensitivity and social deficits. Electrophysiological studies show network hyperexcitability and excitation/inhibition imbalance. The classical complement cascade's role is less clear, with evidence pointing to dysfunction in the CX3CR1- CX3CL1 signaling axis impairing pruning instead. Conversely, schizophrenia exhibits reduced synaptic density in regions like the PFC and hippocampus. Electrophysiological recordings reveal decreased excitatory postsynaptic currents and widespread hypoconnectivity. Strong evidence implicates excessive classical complement cascade activation, especially C4 gene variants, in driving synaptic loss in schizophrenia. These findings highlight a striking neurobiological opposition: ASD appears to involve too little pruning leading to overconnectivity, while schizophrenia involves too much, resulting in synaptic loss. These structural and functional disparities underlie distinct behavioral phenotypes. Crucially, this suggests that a "one-size-fits-all" approach to neurodevelopmental disorder treatment is likely ineffective. Therapies must be tailored to address the specific pruning imbalance present in each condition. Understanding these precise mechanisms is crucial for developing targeted therapeutic strategies and diagnostic biomarkers. Future research should investigate regional specificity of pruning dysfunction, explore the heterogeneity of microglial phenotypes, and develop human-relevant translational models to uncover novel treatments.