βIV spectrin abundancy, cellular distribution and sensitivity to AKT/GSK3 regulation in schizophrenia

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which implicated in SCZ. However, impact of SCZ-related dysregulation this pathway on spectrin expression and distribution remains unexplored. Here, we show that βIV protein levels were reduced neurons dorsolateral prefrontal cortex SCZ postmortem samples compared healthy control (HC) from Human Brain Collection Core (HBCC). To investigate potential links between analyzed PsychEncode dataset, revealing elevated SPTBN4 AKT2 mRNA correlated gene transcription both HCs individuals Next, computational tools employed identify AKT GSK3 phosphorylation sites spectrin, two validated through vitro assays. assess whether sensitivity altered SCZ, used iPSC-derived independent cohorts patients significantly increased familial genetic risk for disorder. Alteration inhibitors consistently observed across cohorts. Importantly, Random Forest classifier applied imaging achieved up 98% accuracy classifying cells diagnosis samples, or × perturbation iPSC samples. These findings reveal identifying image-based endophenotypes as robust, generalizable predictive biomarkers scalable clinical applications.

Language: Английский

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The dynamic axon initial segment: From neuronal polarity to network homeostasis

Neuron, Journal Year: 2025, Volume and Issue: 113(5), P. 649 - 669

Published: Feb. 12, 2025

The axon initial segment (AIS) is a highly specialized compartment in neurons that resides between axonal and somatodendritic domains. localization of the AIS proximal part essential for its two major functions: generating modulating action potentials maintaining neuron polarity. Recent findings revealed incredibly stable generated from dynamic components can undergo extensive structural functional changes response to alterations activity levels. These activity-dependent structure function have profound consequences neuronal functioning, plasticity has emerged as key regulator network homeostasis. This review highlights functions AIS, architecture, how organization remodeling are influenced by developmental both acute chronic adaptations. It also discusses mechanisms underlying these processes explores dysregulated may contribute brain disorders.

Language: Английский

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Contribution of Axon Initial Segment Structure and Channels to Brain Pathology

Cells, Journal Year: 2023, Volume and Issue: 12(8), P. 1210 - 1210

Published: April 21, 2023

Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion specialized proteins play crucial role electrical activity nerve cells by controlling flow ions such as sodium, potassium, and calcium. When these not functioning properly, they can cause wide range symptoms seizures, movement disorders, cognitive impairment. In this context, axon initial segment (AIS) is site action potential initiation most neurons. This region characterized high density voltage-gated sodium (VGSCs), which responsible for rapid depolarization occurs when neuron stimulated. The AIS also enriched other channels, potassium shaping waveform determining firing frequency neuron. addition to contains complex cytoskeletal structure helps anchor place regulate their function. Therefore, alterations scaffold proteins, cytoskeleton may brain necessarily associated with channel mutations. review will focus on how AISs structure, plasticity, composition generate changes potentials neuronal dysfunction leading diseases. function be consequence mutations, but due ligand-activated receptors structural membrane support channels.

Language: Английский

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Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 1, 2023

Abstract The axon initial segment (AIS) constitutes not only the site of action potential initiation, but also a hub for activity-dependent modulation output generation. Recent studies shedding light on AIS function used predominantly post-hoc approaches since no robust murine in vivo live reporters exist. Here, we introduce reporter line which is intrinsically labeled by an ankyrin-G-GFP fusion protein activated Cre recombinase, tagging native Ank3 gene. Using confocal, superresolution, and two-photon microscopy as well whole-cell patch-clamp recordings vitro, ex , confirm that subcellular scaffold electrophysiological parameters cells remain unchanged. We further uncover rapid remodeling following increased network activity this model system, highly reproducible labeling over weeks. This novel allows longitudinal plasticity real-time thus provides unique approach to study broad range applications.

Language: Английский

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Static magnetic stimulation induces structural plasticity at the axon initial segment of inhibitory cortical neurons

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 17, 2024

Abstract Static magnetic stimulation (SMS) is a form of non-invasive brain that alters neural activity and induces plasticity outlasts the period stimulation. This can modify corticospinal excitability or motor behaviours, suggesting SMS may alter intrinsic neurons. In mammalian neurons, axon initial segment (AIS) site action potential initiation undergoes structural (changes in length position from soma) as homeostatic mechanism to counteract chronic changes neuronal activity. We investigated whether application (6 48 h, 0.5 T) AIS postnatally derived primary cortical Following 6 h SMS, we observed shortening mean compared control, persisted 24 post contrast, induced an immediate distal shift post-stimulation. Pharmacological blockade voltage gated L/T-type calcium channels during did not prevent SMS-induced plasticity. Our findings provide foundation expand use method promote

Language: Английский

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