Single-cell study reveals mTOR-linked microglial states in human mTORopathies

Microglia, the resident immune cells of the brain, shape neuronal circuits during development and are central to normal cortical formation. A new single-cell study has mapped how these cells behave in two developmental epilepsy disorders, tuberous sclerosis complex and focal cortical dysplasia type II, both classified as mechanistic target of rapamycin, or mTOR,opathies. These conditions are marked by malformations of cortical development, drug-resistant epilepsy and comorbidities including autism spectrum disorder.

Using single-cell RNA sequencing, researchers identified three distinct mTOR-associated microglial populations in human tissue: lipid-associated disease-associated microglia, known as DAM-like cells, pro-inflammatory microglia, and interferon-responsive DAM-like microglia. The team then confirmed the presence of these populations in cortical tissue samples, moving the findings beyond computational prediction alone.

A key observation was that core transcriptional identities were largely preserved among microglial populations shared between control and mTORopathy samples. What did change was communication. Cell–cell communication analysis revealed disease-specific alterations, particularly involving inhibitory neuronal circuits, suggesting functional reprogramming of the signaling networks that connect microglia with other brain cells.

Disease ontology analysis added another layer of significance. The mTOR-associated microglial populations were linked to both neurodevelopmental and neurodegenerative disorders, indicating that shared microglial activation states may exist across conditions usually studied separately.

The study aimed to characterize the microglial landscape and cell–cell communication networks in mTORopathies, addressing a gap in knowledge about how immune cells contribute to malformations of cortical development. While microglial heterogeneity has been extensively characterized in neurodegenerative disorders, it remains poorly understood in developmental brain disorders such as tuberous sclerosis complex and focal cortical dysplasia type II.

The altered communication involving inhibitory neuronal circuits is particularly relevant to the clinical picture. Drug-resistant epilepsy is a feature of both tuberous sclerosis complex and focal cortical dysplasia type II. The cell–cell communication analysis revealed disease-specific alterations, particularly involving inhibitory neuronal circuits, suggesting functional reprogramming.

Together, these findings reveal distinct microglial states and altered intercellular communication in mTORopathies, providing new insights into microglial dysfunction.

Subject of Research: Single-cell RNA sequencing of microglial populations in human mTORopathies

Article Title: Single-cell discovery of mTOR-associated microglial clusters in human mTORopathies

Article References: Kalf, R. S., Scheper, M., Horst, E. E. T., Anink, J. J., Jansen, F. E., van Hecke, W., Mühlebner, A., van Vliet, E. A., Mills, J. D., & Aronica, E. (2026). Single-cell discovery of mTOR-associated microglial clusters in human mTORopathies. Acta Neuropathologica Communications. https://doi.org/10.1186/s40478-026-02467-9

Image Credits: AI Generated

DOI: 10.1186/s40478-026-02467-9

Keywords: microglia, mTORopathies, tuberous sclerosis complex, focal cortical dysplasia, single-cell RNA sequencing, drug-resistant epilepsy, cortical development, cell–cell communication, disease-associated microglia, autism spectrum disorder, neurodevelopment, interferon-responsive microglia