Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD). We have shown that mild MIR causes chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth with regionally specific volumetric changes, sensory processing dysregulation, and repetitive behavior abnormalities. Prior rapamycin studies in autism models focused on chronic treatments that alter or prevent physical brain changes. Here, we focus on acute rapamycin effects to uncover novel mTOR pathway-mediated mechanisms of dysfunction. Within 2 hours, rapamycin rescues neuronal hyperexcitability, seizure susceptibility, functional network connectivity, brain community structure, repetitive behaviors, and sensory over-responsivity in adult MIR offspring. These CNS-mediated effects coincide with altered expression of genes associated with ASD, ion channels, and epilepsy. Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD-associated brain and behavior phenotypes. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes. Here authors show acute rapamycin transiently rescues neuron hyperexcitability, network connectivity, repetitive behaviors, and sensory over-responsivity in an acquired model of autism, showing mTOR-driven phenotypes can be treatment responsive in the mature brain.
Key links between peripheral protein dysregulation and neuronal function and behavior are revealed, offering new insights into systemic contributions to ASD pathophysiology and highlighting potential therapeutic targets for mitigating symptom severity.
Samia M. Ltaief, Safa Salim, Sadam Hussain et al.· Translational Psychiatry· 0 citations
Altered RAGE signaling is the proposed mechanistic link between ongoing inflammation and impaired oxytocinergic signaling contributing to ASD pathogenesis in certain subgroups.
Jaime Shoup, Charles J. Sadle, A. Buckley et al.· Journal of Translational Med...· 0 citations
Disturbances in GABAergic neurodevelopment are thought to underlie cortical network dysfunction in neurodevelopmental disorders (NDDs) such as autism and schizophrenia. The diversity of GABAergic neurons is shaped by cortical cues during prolonged postmitotic differentiation, yet how pathological environments associated with NDDs influence this process remains poorly understood. Oxysterols, oxidized cholesterol metabolites or its precursors, modulate key developmental signaling pathways. Here, using an iPSC-based model of human forebrain GABAergic neuron differentiation combined with single-cell transcriptomics, we show that 24S,25-epoxycholesterol, an oxysterol enriched in the fetal brain and dysregulated in NDDs, enhances neurogenesis while altering the distribution of GABAergic neuronal subtypes. Pharmacological and genetic perturbations further identify the liver X receptor as a critical mediator of these effects. Together, these findings uncover a link between cholesterol metabolism and GABAergic fate specification, suggesting that aberrant oxysterol signaling contributes to the pathogenesis of NDDs.
Maria Cruz-Santos, E. Kidd, Zongze Li et al.· Translational Psychiatry· 0 citations
The gut microbiota has emerged as a key regulator of central nervous system development and function. Accumulating experimental and clinical evidence demonstrates that microbial signals influence brain activity through integrated neural, immune, neuroendocrine, and metabolic pathways. These pathways converge on core mechanisms of synaptic plasticity, including neurotrophic signaling, glutamatergic transmission, dendritic remodeling, and adult neurogenesis, thereby shaping learning, memory, executive function, and emotional regulation. Disruption of microbiota-brain communication is implicated in a range of neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting shared systems-level vulnerabilities across conditions and highlighting the translational potential of microbiota-targeted interventions such as probiotics, dietary modulation, postbiotics, and precision microbiome-based strategies. Overall, the gut microbiota functions as a dynamic regulator of brain plasticity and cognitive resilience across the lifespan. Future progress will require identification of causal mechanisms at the level of specific microbial metabolites, neural circuits, and developmental windows using integrated multi-omics and spatially resolved approaches, alongside translation into targeted therapeutic strategies.
Chronic pain is a multifaceted condition characterized by persistent nociceptive signaling and maladaptive central nervous system plasticity, in which the hippocampus has emerged as a critical hub of structural, functional, metabolic, and molecular remodeling. This review systematically synthesizes current evidence on hippocampal alterations in chronic pain across multiple levels, including structural remodeling (e.g., gray matter atrophy and impaired neurogenesis), functional and circuit-level disruptions, metabolic dysregulation, and cellular and molecular mechanisms. In particular, we highlight convergent pathways involving neurotransmitter and receptor dysregulation, cytokine-driven neuroinflammation, neurotrophic signaling deficits, and additional molecular alterations that collectively impair synaptic plasticity and hippocampal network stability. Importantly, we propose a multiscale integrative framework in which synaptic imbalance, neuroimmune activation, and neurotrophic dysregulation interact to drive hippocampal dysfunction, forming a bidirectional loop that links pain, emotion, and cognition. We further discuss therapeutic strategies targeting hippocampal remodeling, including pharmacological, metabolic, neuroimmune, and circuit-level neuromodulation approaches, as well as emerging precision medicine strategies. By integrating preclinical and clinical evidence, this review positions the hippocampus as a central node in chronic pain pathophysiology and a promising target for developing interventions that address both nociceptive and comorbid affective and cognitive symptoms. These insights support a unified model of hippocampal remodeling in chronic pain that may guide future precision diagnostics and targeted interventions.
Neuroinflammation has emerged as a fundamental driver of neural circuit dysfunctions across a spectrum of neurodevelopmental and psychiatric disorders. Beyond classical neuroimmune pathologies, accumulating evidence indicates that systemic inflammatory states - including those elicited by infection, metabolic dysfunction, stress, or peripheral immune activation - induce profound and long-lasting alterations in brain development and function. Cytokines act as critical molecular mediators of this peripheral-to-central immune communication, precisely orchestrating microglial activation in a spatiotemporally restricted manner. Inflammasome-dependent signaling, particularly NLRP3 activation and subsequent cytokine release, has a central role in shaping microglial states during neuroinflammation. Here, we integrate current evidence linking systemic inflammation to microglial cytokine signaling programs and discuss how these cascades shape synaptic development, refinement, and circuit function. Although synapse pruning and cytokine-mediated microglial signaling jointly contribute to circuit remodeling, we highlight cytokine-driven microglial state amplification as a central mechanism linking systemic inflammation to neural circuit instability. We also highlight that specific cytokines can exert direct effects on neuronal populations - independent of microglial intermediates - to context-dependently modulate synaptic efficacy and circuit excitability. Finally, we evaluate the mechanisms linking systemic inflammation to brain dysfunction and highlight emerging translational opportunities, including the therapeutic repurposing of cytokine-targeting and immunomodulatory agents for neuropsychiatric interventions.
Yelin Lee, Jaewon Ko, J. Um· Experimental and Molecular M...· 0 citations