{"i":"SCN2A","#text":"Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carryingmutation."}

Scientists created lab-grown brain tissue with immune cells called microglia to study autism. They found that in brains with an autism-linked gene mutation (SCN2A), these immune cells become overactive and remove too many brain connections. However, when researchers blocked certain receptors on these cells, the harmful effects were reversed, suggesting a possible new treatment approach.

This study developed innovative brain organoids incorporating human microglia to investigate their role in autism-related brain circuits. Researchers created region-specific organoids (cortical, striatal, midbrain) and identified six distinct microglial subtypes with unique regional properties. Using assembloids modeling midbrain-striatal circuits, they examined microglial responses to SCN2A mutations associated with autism. Results showed that microglia exhibited heightened responses to mutation-induced neuronal hyperactivity and engaged in excessive synaptic pruning.

These pathological effects were reversed by targeting microglial GABA receptors, either pharmacologically or through gene knockout, suggesting potential therapeutic targets for autism interventions.

Findings suggest microglial GABA receptors as novel therapeutic targets for SCN2A-related autism. The reversibility of pathological effects offers hope for intervention strategies. However, translation to clinical applications requires further validation in animal models and human studies.

Sample size not reported. Study uses in vitro organoid models which may not fully recapitulate complex in vivo brain interactions. Findings specific to SCN2A mutations may not generalize to other autism subtypes.

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAreceptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism.

Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAreceptors. Leveraging this model, we examined microglial responses within neural circuits harboring annonsense (C959X) mutation associated with profound autism. Microglia displayed heightened calcium responses tomutation-mediated neuronal hyperactivity and engaged in excessive synaptic pruning. These pathological effects were reversed not only by pharmacological inhibition of microglial GABAreceptors but also by knockout of thegene in microglia.

Collectively, our findings establish an advanced platform that can be used to dissect human neuroimmune interactions in subcortical regions and to evaluate previously undiscovered therapies, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders.