This review integrates findings from studies across various model organisms to elucidate how alterations in synaptic function disrupt social interaction, and discusses the use of drugs and gene therapies in the management and treatment of the symptoms observed in social interaction disorders.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and repetitive behaviors, now affecting approximately 1 in 31 children. While traditionally defined behaviorally, ASD is increasingly understood as a disorder of brain connectivity arising from altered synaptic formation and refinement. This narrative review synthesizes evidence on neuroimmune dysregulation in ASD, focusing on immune-mediated synaptic pruning mechanisms. We conducted a comprehensive literature search in PubMed, Scopus, and Web of Science (2010–2026), prioritizing high-impact peer-reviewed research. Convergent findings suggest that the classical complement cascade (C1q-C3) tags specific synapses for elimination, while microglia participate in the phagocytic removal of tagged connections. Genetic studies have reported associations between ASD and variants in complement-related genes (C1q, C3, CR3, and C4A, although the strongest evidence for C4A-mediated pruning comes from schizophrenia research), as well as in microglial function genes (TREM2, PTEN, SHANK3). Neuroimaging reveals a dynamic pattern of local hyperconnectivity transitioning to long-range hypoconnectivity during development, particularly affecting prefrontal, insular, and cerebellar regions. Systemic inflammation, including gut–brain axis dysbiosis and maternal immune activation, may amplify neuroimmune dysregulation. We conclude that ASD can be understood, in part, as a disorder of synaptic immunology, where disrupted neuroimmune communication during critical developmental windows may contribute to altered connectivity. The complement–microglia axis therefore represents a potential mechanistic target for future therapeutic investigation.
The framework used to evaluate the relevance of animal models-construct, face, and predictive validity-is outlined and the behavioural paradigms used to assess core ASD-related domains in rodents are summarized, including social interaction and communication, restricted and repetitive behaviours, and cognitive flexibility.
Pilar Martinez Olondo, Alban de Kerchove d'Exaerde· Developmental Medicine & Chi...· 0 citations
A neuroimmune–cognitive account of ASD is developed by examining how immune signaling may influence neural organization and, in turn, cognitive function, and testable hypotheses concerning how immune processes may influence neural organization and cognition in ASD are generated.
Sherif Ganem, Gerry Leisman, R. Melillo· International Journal of Cog...· 0 citations
This study provides substantial evidence for the vital role of trip12 in the early stages of development, as homozygous individuals exhibited early mortality by Day 23 post-fertilization, while a substantial mortality rate was observed by Day 35 in ‘heterozygous’ mutants.
Maider Roibás-Santos, P. Suarez-Bregua, J. Rotllant et al.· Brain Communications· 0 citations
This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT.
P. Pattnaik, S. Prusty, Sanghamitra Pati et al.· Gene· 0 citations
