Autism-relevant oxysterol signaling regulates GABAergic neurogenesis and interneuron subtype specification

Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene and characterized by profound impairments in neuronal maturation and synaptic connectivity. Increasing evidence indicates that astrocyte dysfunction contributes to RTT pathogenesis through non-cell-autonomous mechanisms, although the molecular pathways underlying defective astrocyte-neuron communication are only partially understood. Astrocytes are the primary source of cholesterol in the brain and support neuronal maturation and synaptic function by supplying cholesterol through ApoE-containing lipoproteins. Although alterations in brain cholesterol metabolism have been reported in RTT, the underlying cellular mechanisms and their functional consequences remain poorly investigated. Here, we studied cholesterol homeostasis in Mecp2 knock-out (KO) astrocytes and its impact on neuron-astrocyte communication. Mecp2 KO astrocytes exhibited reduced nuclear localization of the transcriptional regulator Srebp2, together with the downregulation of genes involved in cholesterol biosynthesis and transport. These molecular alterations were associated with intracellular cholesterol and desmosterol accumulation, reduced Abca1 expression and defective ApoE lipidation, despite preserved ApoE expression and cholesterol secretion. Importantly, similar alterations were detected in acutely isolated astrocytes and in the cerebral cortex of Mecp2 deficient mice, demonstrating that impaired cholesterol homeostasis extends beyond in vitro models. Functionally, cholesterol supplementation of astrocyte-conditioned medium rescued the synaptic defects induced in wild-type neurons by Mecp2 KO astrocytes. Moreover, cholesterol treatment restored pre- and post-synaptic density, as well as axon initial segment length in Mecp2 heterozygous (HET) neurons. Together, these findings identify defective astrocyte-to- neuron cholesterol trafficking as a key mechanism contributing to neuronal dysfunction in RTT and suggest that strategies aimed at restoring cholesterol functional availability might represent a promising therapeutic avenue for RTT.

Esculetin ameliorates autism-like behaviors in GABAergic neuron-specific Pax2 knockdown mice, accompanied by reduced Wnt/β-catenin signaling.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unclear pathogenesis. Growing evidence implicates excitatory/inhibitory (E/I) imbalance in ASD pathophysiology, prompting an investigation into gamma-aminobutyric acid (GABA)-mediated inhibitory transmission. The transcription factor Paired Box 2 (Pax2), essential for GABAergic interneuron specification, participates in the regulation of neural developmental processes. Our previous work demonstrated an E/I imbalance in the neurotransmitter system and reduced GABAARα2-positive neurons in the prefrontal cortex (PFC) of Pax2 neuron-specific deletion mice, though the internal molecular regulatory mechanism remained elusive. In this study, we generated GABAergic neuron-specific Pax2 knockdown mice via injection of AAV-shPax2 virus and comprehensively evaluated ASD-related behaviors, revealing autism-like behaviors, such as impaired social novelty and repetitive behaviors. Molecular analysis revealed upregulation of Tcf7l2, a key downstream mediator of the Wnt/β-catenin signaling pathway. Functional assessment confirmed hyperactivation of the Wnt/β-catenin signaling pathway in GABAergic neuron Pax2 knockdown mice. Notably, pharmacological intervention with esculetin, an inhibitor of the Wnt/β-catenin pathway, ameliorated the observed autism-like behaviors. These findings establish a pathogenic axis wherein GABAergic neuron-specific Pax2 deficiency induces hyperactivation of the Wnt/β-catenin signaling pathway and disrupts E/I balance, ultimately driving autism-like behavioral phenotypes. Our results further identify inhibition of Wnt/β-catenin signaling as a promising therapeutic strategy for ASD.

Gestational Hypoxia Disrupts Medial Ganglionic Eminence Progenitor Dynamics and Interneuron Development in Schizophrenia

ABSTRACT Schizophrenia (SCZ) is a neurodevelopmental disorder characterized by heterogeneous symptoms and multifactorial etiologies. Medial ganglionic eminence (MGE) spheroids generated from first‐episode schizophrenia (FES) patients revealed accelerated neurodevelopmental trajectories and enhanced hypoxia responses via single‐cell transcriptomics. Notably, FES patient‐derived MGE spheroids exhibited defective interneuron migration, disrupted synaptic ultrastructure, and diminished network synchronization. To establish causal links, the gestational hypoxia mouse model recapitulated key pathologies, including reduced progenitor proliferation, abbreviated cell cycles, mismatched interneuron subtypes, and schizophrenia‐like behavioral deficits in offspring. Critically, maternal administration of N‐acetylcysteine (NAC) restored redox homeostasis and rescued both cellular and behavioral phenotypes. Collectively, these results demonstrate that developmental redox disruption directly impairs GABAergic circuit assembly, while supporting targeted antioxidant pharmacotherapy during gestation as a translatable strategy to mitigate neurodevelopmental risk.

A vicious cycle of microglial dysfunction: bridging synaptic pruning and neuroinflammation across the neurodevelopmental continuum

Rather than viewing classical neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and severe psychiatric illnesses like schizophrenia (SCZ) as isolated diagnostic silos, modern biological psychiatry increasingly conceptualizes them along a shared neurodevelopmental continuum. Although altered synaptic connectivity and sustained immune dysregulation are both well-documented pathological features, the mechanistic crosstalk between them remains incompletely understood. In this review, we propose that microglia occupy a central position at the interface of these processes because of their dual roles in circuit remodeling and immune surveillance. While individual components, including complement-mediated pruning and inflammasome activation, have been extensively studied, the novelty of our framework lies in integrating these fragmented findings into a cohesive, bidirectional Dysregulated Pruning-Neuroinflammation Cycle to describe how the disruption of microglial homeostasis can sustain a self-perpetuating pathological loop. In this model, the vicious cycle may be initiated through an Outside-In route in which environmental inflammatory insults disrupt synaptic pruning, or through an Inside-Out route in which aberrant synaptic elimination releases danger signals that promote neuroinflammation. By considering early-onset ASD and adolescent/early-adult-onset SCZ, we propose that the interplay among timing, patterning, and background biases neurodevelopmental trajectories toward distinct clinical outcomes. Accordingly, this model highlights disease-modifying therapeutic strategies aimed at restoring microglial homeostasis to potentially mitigate the self-sustaining pathology in these clinically significant neurodevelopmental and psychiatric disorders.

The potential role of aberrant microglial synaptic pruning in the neurodevelopmental pathogenesis of tourette syndrome

Tourette syndrome is a neurodevelopmental disorder traditionally attributed to dopamine system hyperactivity within the cortico-striato-thalamo-cortical circuitry. However, classical neurotransmitter hypotheses fail to fully explain the spatiotemporal and developmental specificities of the disorder. Consequently, research focus has shifted toward the neuroimmune microenvironment, specifically the role of microglia. This review aims to comprehensively explore the potential mechanisms of microglia-mediated aberrant synaptic pruning in the pathogenesis of tourette syndrome and to evaluate emerging therapeutic strategies. Methodologically, the study employs a narrative review approach to synthesize current neuroimmunobiology literature to reconstruct the pathological trajectory from early immune dysregulation to targeted interneuron impairment. Additionally, it conceptually explores natural product active monomers through a multi-target network pharmacology framework and assesses the translational potential of engineered nanodelivery systems. The findings indicate that genetic susceptibilities, such as histidine decarboxylase gene mutations, interact with environmental stressors, like maternal immune activation, to induce a chronically primed state in basal ganglia microglia. These primed innate immune cells are hypothesized to execute excessive synaptic pruning against highly vulnerable parvalbumin-expressing fast-spiking interneurons, a process significantly facilitated by the pathological downregulation of presynaptic protective signals. The physical loss of this local gamma-aminobutyric acid-ergic inhibitory network attenuates feedforward inhibition on medium spiny neurons, potentially contributing to macroscopic dopaminergic disinhibition. To address these mechanisms, multi-target natural therapies delivered via intelligent nanoplatforms present a theoretically promising approach to penetrate the blood–brain barrier and reverse pathological microglial phenotypes. Ultimately, this manuscript proposes a perspective of tourette syndrome as a microstructural developmental disorder of the circuitry rather than a mere neurotransmitter imbalance, providing a critical theoretical foundation for developing precise, next-generation neuroimmune-modulating interventions.

Astroglial dysregulation and gliotransmitter imbalance in schizophrenia.