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نمایش مقاله

Title:

Mapping Hippocampal Changes Related to mTOR Signaling in Autism Spectrum Disorder: A Systematic Review

Subject:

Autism and Brain Mapping

Presenter Author:
Name:	PARMIDA SERAJ

Author:
Name 1:	PARMIDA SERAJ - Corresponding - Presenter
Affiliation 1:	Medical student, Department of Medicine, Tehran Medical Branch, Islamic Azad University, Tehran, Iran

Name 2:	Sadra Hoseini
Affiliation 2:	Medical student, Department of Medicine, Tehran Medical Branch, Islamic Azad University, Tehran, Iran

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Abstract

Original Research

introduction :

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social-communication difficulties and repetitive behaviors. Converging evidence implicates dysregulation of the mTOR pathway, particularly mTORC1 hyperactivity seen in tuberous sclerosis complex (TSC), in abnormal synaptic plasticity and neurodevelopment. Because the hippocampus is central to learning, memory, and neuroplasticity, it is a plausible target through which mTOR-related mechanisms may contribute to ASD-relevant phenotypes.

Methods:

This systematic review was prospectively registered in PROSPERO (Registration No.CRD420251110264) and conducted in accordance with PRISMA 2020 and the Cochrane Handbook (22 July 2025). A comprehensive search of PubMed, Scopus, Web of Science, and Embase (January 2015–July 2025) identified studies examining the impact of mTOR inhibition on hippocampal structure in autism. Search terms integrated MeSH and free-text keywords encompassing mTOR inhibitors (rapamycin, sirolimus, everolimus, temsirolimus, ridaforolimus) and hippocampal subfields (CA1, CA3, dentate gyrus, subiculum). Eligible studies included randomized controlled trials and cohort designs in humans or in vivo murine autism models reporting neuroimaging or histological hippocampal outcomes. Exclusion criteria comprised in vitro studies, non-murine models, combined drug interventions without separate results, and non-English or non-peer-reviewed sources. Of 1,109 records retrieved, 199 duplicates were removed, leaving 910 for screening; 7 met inclusion criteria for full-text review, and 5 reported neuroimaging outcomes relevant to hippocampal morphology. Data extraction and risk-of-bias assessment were independently performed by two reviewers using standardized forms and validated tools (SYRCLE). Owing to methodological heterogeneity, findings were synthesized narratively, emphasizing structural and neuroplastic hippocampal alterations linked to mTOR modulation in autism.

Results:

Five preclinical studies investigating hippocampal outcomes related to mTOR pathway modulation in autism spectrum disorder (ASD) were included. One study used in vivo diffusion tensor imaging (DTI), two employed in vivo murine models with hippocampal histological and behavioral outcomes, and two were in vitro mechanistic studies. No human neuroimaging studies were identified. The only neuroimaging study demonstrated hippocampal microstructural abnormalities in a Tsc2+/− mouse model, primarily within the CA1 subfield, characterized by altered fractional anisotropy and mean diffusivity. Chronic dietary curcumin, acting as an mTORC1 inhibitor, normalized these DTI alterations and reduced downstream mTOR activity. Histological studies showed that downregulation of mTOR signaling enhanced hippocampal neurogenesis in the dentate gyrus and was associated with improvements in autism-like behaviors, including social interaction, memory, and anxiety-related outcomes. In contrast, pathological activation of mTOR signaling led to abnormal dendritic architecture, impaired synaptic organization, or microglia-mediated hippocampal neuron injury. Across studies, beneficial hippocampal and behavioral effects were consistently observed when mTOR activity was reduced, whereas mTOR overactivation was associated with adverse hippocampal outcomes.

Conclusion:

Current evidence linking mTOR pathway modulation to hippocampal alterations in ASD is limited and largely preclinical. Only one study provides direct neuroimaging evidence of hippocampal microstructural rescue following mTOR inhibition. Nevertheless, converging findings from imaging, histological, and behavioral studies suggest that excessive mTOR signaling contributes to hippocampal pathology relevant to autism, while its downregulation may restore hippocampal integrity and function. Well-designed human neuroimaging studies are needed to clarify the translational relevance of these findings and to evaluate mTOR-targeted interventions as potential therapeutic strategies in ASD.

Keywords:

mTOR pathway, Autism spectrum disorder (ASD), Diffusion tensor imaging (DTI), Neuroimaging biomarkers