Neurodevelopmental disorders (NDDs) include various neurological disorders with high genetic heterogeneity, characterized by delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills. These disorders result in significant morbidity for children, thus burdening families and healthcare/educational systems. However, there is a lack of early diagnosis and effective therapies. Therefore, a more connected approach is required to explore these disorders. Microglia, the primary phagocytic cells within the central nervous system, are crucial in regulating neuronal viability, influencing synaptic dynamics, and determining neurodevelopmental outcomes. Although the neurobiological basis of autism spectrum disorder (ASD) and schizophrenia (SZ) has attracted attention in recent decades, the role of microglia in ASD and SZ remains unclear and requires further discussion. In this review, the important and frequently multifaceted roles that microglia play during neurodevelopment are meticulously emphasized and potential microglial mechanisms that might be involved in conditions such as ASD and SZ are postulated. It is of utmost importance to acquire a comprehensive understanding of the complexities of the interplay between microglia and neurons to design effective, targeted therapeutic strategies to mitigate the effects of NDDs.

The supramammillary nucleus (SuM), a ventromedial structure of the posterior hypothalamus, has long been viewed primarily as a pacemaker for hippocampal theta rhythms. Recent discoveries, however, reveal pronounced cellular heterogeneity within the SuM and demonstrate that distinct neuronal subpopulations engage projection-defined pathways to shape hippocampal dynamics, septo-hippocampal state regulation, and broader limbic processing. Through these mechanisms, SuM activity influences adult hippocampal neurogenesis, memory encoding and retrieval, affective regulation, and behavioral state transitions in a context-dependent manner. Rather than acting as a uniform modulatory source, the SuM appears to integrate internal state signals, including arousal, metabolic, and motivational cues, and route them through parallel output channels to exert coordinated control over cognitive and emotional functions. Here, we synthesize recent advances in SuM cellular diversity, intrinsic microcircuit logic, and long-range connectivity, and propose a unifying framework in which the SuM operates as a systems-level hub whose dysregulation may contribute to neuropsychiatric and neurodegenerative disorders. This perspective highlights both conceptual gaps in current understanding and emerging opportunities for pathway-informed neuromodulation strategies.

Fragile X syndrome (FXS) is the predominant singlegene cause of inherited intellectual disability and is strongly associated with autism spectrum disorder (ASD). FXS results from the disruption of fragile X messenger ribonucleoprotein 1 gene (FMR1) and is characterized by synaptic dysfunction manifesting as impaired cognitive function and social communication. The Wnt/β-catenin pathway plays a pivotal role in regulating synaptic structural remodeling and functional homeostasis, critically contributing to higher-order neural processes such as learning and memory. Studies have identified glycogen synthase kinase 3 beta (GSK3β), a key negative regulator of Wnt signal transduction, is abnormally activated in the pathophysiology of FXS, and demonstrated that GSK3β inhibition partially rescues cognitive and behavioral deficiencies in FXS mice. However, the spatiotemporal dysregulation of β-catenin dynamics and its synaptic consequences remain poorly understood. Here, we investigated the role and molecular mechanism of Wnt/β-catenin pathway during developmental stages in FXS using Fmr1 gene knockout (Fmr1 KO) mice. We systematically explored β-catenin homeostasis across subcellular compartments. Our results showed increased phosphorylation of β-catenin at Ser^33,37, Thr⁴¹ and Ser⁵⁵² residues, which fosters its degradation. This was accompanied by reduced levels of active β-catenin in the membrane, cytoplasm and nucleus within the hippocampus (Hipp) and prefrontal cortex (PFC) of Fmr1 KO mice. Confocal microscopy further demonstrated diminished co-localization of β-catenin with N-cadherin, leading to compromised intercellular adhesion in both Fmr1 KO neurons. Moreover, FXS mice showed impaired neuronal morphology and deficiencies in social and cognitive functions, which were associated with the downregulation of pre- and postsynaptic proteins targeted by Wnt pathway. Strikingly, pharmacological activation of Wnt signal transduction restored β-catenin nuclear translocation and synaptic protein expression, rescued neuronal ultrastructural abnormalities and improvd cognitive and social behaviors. Our findings establish hypoactivity of canonical Wnt signaling as a central mechanism underlying synaptic pathology in FXS, linking β-catenin destabilization to altered neuronal morphology, aberrant synaptic protein networks, and behavioral phenotypes. Consequently, bolstering Wnt pathway may represent a promising neuroprotective strategy for precision intervention in FXS.