Human pluripotent stem cell (hPSC)-derived models for autism spectrum disorder drug discovery DOI
Lingdi Nie, Courtney Irwin,

Sarah Geahchan

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 19

Published: Dec. 24, 2024

Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental (NDD) with genetic environmental origins. Currently, there are no effective pharmacological treatments targeting core ASD features. This leads to unmet medical needs of individuals requires relevant human disease models recapitulating clinical heterogeneity better understand underlying mechanisms identify potential therapies. Recent advancements in stem cell technology have enabled the generation pluripotent (hPSC)-derived two-dimensional (2D) three-dimensional (3D) neural models, which serve as powerful tools for modeling drug discovery.

Language: Английский

Advancements in 3D models for studying human iPSC-microglia: Insights into neurodevelopment and neurological disorders DOI Creative Commons
Satish Kumar Tiwari, Florent Ginhoux

hLife, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

1
Untangling the Molecular Mechanisms Contributing to Autism Spectrum Disorder Using Stem Cells DOI Open Access

Zoe A. Mattingly,

Sundari Chetty

Autism Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Autism spectrum disorder (ASD) is a complex neuro developmental condition characterized by significant genetic and phenotypic variability, making diagnosis treatment challenging. The heterogeneity of ASD-associated variants the absence clear causal factors in many cases complicate personalized care. Traditional models, such as postmortem brain tissue animal studies, have provided valuable insights but are limited capturing dynamic processes human-specific aspects ASD pathology. Recent advances human induced pluripotent stem cell (iPSC) technology transformed research enabling generation patient-derived neural cells both two-dimensional cultures three-dimensional organoid models. These models retain donor's background, allowing researchers to investigate disease-specific cellular molecular mechanisms while identifying potential therapeutic targets tailored individual patients. This commentary highlights how cell-based approaches advancing our understanding paving way for more diagnostic strategies.

Language: Английский

Citations

1
Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associatedScn2a-deficiency DOI Creative Commons
Jingliang Zhang, Muriel Eaton, Xiaoling Chen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Social behavior is critical for survival and adaptation, which profoundly disrupted in autism spectrum disorders (ASD). withdrawal due to information overload was often described ASD, it suspected that increased basal noise, i.e., excessive background neuronal activities the brain could be a disease mechanism. However, experimental test of this hypothesis limited. Loss-of-function mutations (deficiency) SCN2A , encodes voltage-gated sodium channel Na V 1.2, have been revealed as leading monogenic cause profound ASD. Here, we Scn2a deficiency results robust multifaceted social impairments mice. -deficient neurons displayed an excitation-inhibition (E/I) ratio, contributing elevated noise diminished signal-to-noise ratio (SNR) during interactions. Notably, restoration expression adulthood able rescue both SNR deficits. By balancing E/I reducing firing, FDA-approved GABA A receptor-positive allosteric modulator improves sociability mice normalizes translationally relevant human organoids carrying autism-associated nonsense mutation. Collectively, our findings role 1.2 regulation behaviors, identified molecular, cellular, circuitry mechanisms underlying -associated disorders. leads pronounced deficits overall enhanced activity, impaired ratio. Both are reversible through adulthood. Targeted striatum-projecting rescues impairments. transmission reduced mouse organoid models deficiency, acute systemic administration modulators restores sociability. Graphical abstract: Severe predominate decrease with SNR, adult 1.2-deficient

Language: Английский

Citations

1
Microglia as hunters or gatherers of brain synapses DOI

Marta Pereira-Iglesias,

Joel Maldonado-Teixidó,

Alejandro Melero

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Language: Английский

Citations

8
Neuroplasticity of children in autism spectrum disorder DOI Creative Commons
Zilin Chen,

Xu Wang,

Si Zhang

et al.

Frontiers in Psychiatry, Journal Year: 2024, Volume and Issue: 15

Published: April 25, 2024

Autism spectrum disorder (ASD) is a neurodevelopmental that encompasses range of symptoms including difficulties in verbal communication, social interaction, limited interests, and repetitive behaviors. Neuroplasticity refers to the structural functional changes occur nervous system adapt respond external environment. In simpler terms, it brain's ability learn new environments. However, individuals with ASD exhibit abnormal neuroplasticity, which impacts information processing, sensory cognition, leading manifestation corresponding symptoms. This paper aims review current research progress on focusing genetics, environment, neural pathways, neuroinflammation, immunity. The findings will provide theoretical foundation insights for intervention treatment pediatric fields related ASD.

Language: Английский

Citations

6
Advancing Brain Organoid Electrophysiology: Minimally Invasive Technologies for Comprehensive Characterization DOI Creative Commons
Mujeeb Yousuf, Jean‐Christophe Rochet, Pushpapraj Singh

et al.

Advanced Materials Technologies, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Abstract Human brain organoids, which originate from pluripotent stem cells, serve as valuable tools for a wide range of research endeavors, replicating function. Their capacity to replicate cellular interactions, morphology, and division provides invaluable insights into development, disease modeling, drug screening. However, conventional morphological analysis methods are often invasive lack real‐time monitoring capabilities, posing limitations achieving comprehensive understanding. Therefore, advancing the comprehension organoid electrophysiology necessitates development minimally measurement technologies with long‐term, high‐resolution capabilities. This review highlights significance human organoids emphasizes need electrophysiological characterization. It delves assessment methods, particularly focusing on 3D microelectrode arrays, electrode insertion mechanisms, importance flexible arrays facilitate recordings. Additionally, various sensors tailored monitor properties introduced, enriching understanding their chemical, thermal, mechanical dynamics.

Language: Английский

Citations

0
PDE4 inhibition alleviates HMGB1/C1q/C3-mediated excessive phagocytic pruning of synapses by microglia and depressive-like behaviors in mice DOI
Qian Zhao,

Chunyuan Zeng,

Fulan Luo

et al.

Brain Behavior and Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
Clec7a Signaling in Microglia Promotes Synapse Loss Associated with Tauopathy DOI Open Access
Sheng Yang, Ji Wang,

Yongkang Cao

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2888 - 2888

Published: March 22, 2025

Alzheimer's disease (AD) pathogenesis involves progressive synaptic degeneration, a process potentially driven by maladaptive microglial pruning activity. While loss is hallmark of AD, the molecular signals triggering pathological microglia-mediated engulfment remain elusive. Clec7a-a key marker disease-associated microglia (DAM)-is known to activate spleen tyrosine kinase (SYK) signaling, enhancing Aβ phagocytosis and neuroprotective functions in 5×FAD models. However, its role regulating synapse-microglia interactions under tauopathic conditions remains undefined. Our analysis revealed activation Clec7a-SYK signaling axis hippocampus PS19 tauopathy mice, correlating with progression. Spatial mapping demonstrated significant co-localization Clec7a hippocampal microglia, suggesting cell-autonomous signaling. The pharmacological inhibition achieved multimodal therapeutic effects attenuating hyperreactivity, suppressing neuroinflammatory cytokine release, restoring physiological turnover. Mechanistically, we identified MD2 as "eat-me" signal on tauopathy-related synapses, recruiting Clec7a+ drive aberrant elimination mice. Strikingly, blockade rescued hippocampal-dependent memory deficits behavioral tests. These findings position context-dependent target, strategies showing particular promise for degeneration.

Language: Английский

Citations

0
The “don’t eat me” signal CD47 is associated with microglial phagocytosis defects and autism-like behaviors in 16p11.2 deletion mice DOI Creative Commons
Jun Ju, Yifan Pan,

Xinyi Yang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(16)

Published: April 16, 2025

Various pathological characteristics of autism spectrum disorder (ASD) stem from abnormalities in brain resident immune cells, specifically microglia, to prune unnecessary synapses or neural connections during early development. Animal models ASD exhibit an abundance different regions, which is strongly linked the appearance behaviors. Overexpression CD47 on neurons acts as a “don’t eat me” signal, safeguarding inappropriate pruning by microglia. Indeed, overexpression occurs 16p11.2 deletion carriers, causing decreased synaptic phagocytosis and manifestation characteristics. However, role impairment leading phenotypes mouse model unclear. Moreover, whether blocking can alleviate mice’s behavioral deficits remains unknown. Here, we demonstrate strong link between increased expression, microglia capacity, social novelty preference mice. The reduction caused rise excitatory transmission prefrontal cortex Importantly, using specific antibody reducing expression short hairpin RNA (shRNA) enhanced reduced transmission. Reduction improved These findings that associated with mice could be promising target for development treatment ASD.

Language: Английский

Citations

0
Loss of insulin signaling in microglia impairs cellular uptake of Aβ and neuroinflammatory response exacerbating AD-like neuropathology DOI Creative Commons

Wenqiang Chen,

Xiangyu Liu,

Vitor Rosetto Muñoz

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(21)

Published: May 19, 2025

Insulin receptors are present on cells throughout the body, including brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated altered mood, cognition, pathogenesis Alzheimer’s disease (AD). To define role microglia, primary phagocytes brain critical for maintenance damage repair, we created mice with an inducible microglia-specific receptor knockout (MG-IRKO). RiboTag profiling microglial mRNAs revealed that loss results alterations gene expression pathways related to innate immunity cellular metabolism. In vitro, microglia metabolic reprogramming increase glycolysis impaired uptake Aβ. vivo, MG-IRKO exhibit mood social behavior, when crossed 5xFAD mouse model AD, resultant increased levels Aβ plaque elevated neuroinflammation. Thus, plays a key metabolism ability take up Aβ, such reduced alters behavior accelerates AD pathogenesis. Together, these data indicate roles action potential targeting treatment AD.

Language: Английский

Citations

0