Astrocytic LRRK2 Controls Synaptic Connectivity through ERM Phosphorylation DOI Creative Commons
Shiyi Wang, Ryan Baumert, Gabrielle Séjourné

et al.

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

Published: April 10, 2023

SUMMARY Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson’s Disease (PD) is unknown. Here, we investigated impact most common PD-linked mutation leucine-rich repeat kinase 2 ( LRRK2 ) gene (G2019S) on functions astrocytes. We found that both human mouse cortex, G2019S causes morphology deficits enhances phosphorylation ERM proteins (Ezrin, Radixin, Moesin), which are important components perisynaptic processes. Reducing astrocytes restored corrected excitatory deficits. Using an vivo BioID proteomic approach, Ezrin, abundant astrocytic protein, interacts with Autophagy-Related 7 (Atg7), master regulator catabolic The Ezrin/Atg7 interaction inhibited by Ezrin phosphorylation, thus diminished Importantly, Atg7 function required to maintain proper morphology. These studies reveal molecular mechanism could serve therapeutic target PD.

Language: Английский

δ-Catenin controls astrocyte morphogenesis via layer-specific astrocyte–neuron cadherin interactions DOI Creative Commons
Christabel Xin Tan,

Dhanesh Sivadasan Bindu,

Evelyn J. Hardin

et al.

The Journal of Cell Biology, Journal Year: 2023, Volume and Issue: 222(11)

Published: Aug. 29, 2023

Astrocytes control the formation of specific synaptic circuits via cell adhesion and secreted molecules. Astrocyte synaptogenic functions are dependent on establishment their complex morphology. However, it is unknown if distinct neuronal cues differentially regulate astrocyte morphogenesis. δ-Catenin was previously thought to be a neuron-specific protein that regulates dendrite We found δ-catenin also highly expressed by astrocytes required both in neurons for hypothesized mediate transcellular interactions through cadherin family proteins. used structural modeling biochemical analyses reveal interacts with N-cadherin juxtamembrane domain promote surface expression. An autism-linked point mutation impaired expression reduced complexity. In developing mouse cortex, only lower-layer cortical express N-cadherin. Remarkably, when we silenced astrocytic throughout morphology disrupted. These findings show controls astrocyte-neuron layer-specific

Language: Английский

Citations

21
Structural neural plasticity evoked by rapid-acting antidepressant interventions DOI
Clara Liao, Alisha N. Dua,

Cassandra Wojtasiewicz

et al.

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

Published: Nov. 18, 2024

Language: Английский

Citations

8
Ganglioside GT1b prevents selective spinal synapse removal following peripheral nerve injury DOI Creative Commons
Jaesung Lee, Kyungchul Noh,

Subeen Lee

et al.

EMBO Reports, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

After peripheral nerve injury, the structure of spinal cord is actively regulated by glial cells, contributing to chronicity neuropathic pain. However, mechanism which injury leads synaptic imbalance remains elusive. Here, we use a pH-reporter system and find that triggers reorganization excitatory synapses influenced accumulation ganglioside GT1b at afferent terminals. acts as protective signal against injury-induced synapse elimination. Inhibition GT1b-synthesis increases phagocytosis pre-synapses reduces post-injury. In vitro analyses reveal positive correlation between frequency pre-synaptic calcium activity, with GT1b-mediated suppression occurring through SYK dephosphorylation. Our study highlights GT1b's pivotal role in preventing elimination after offers new insight into molecular underpinning activity-dependent stability phagocytosis.

Language: Английский

Citations

0
Selectively vulnerable deep cortical layer 5/6 fast-spiking interneurons in Alzheimer’s disease models in vivo DOI Creative Commons
Amalia Papanikolaou, David Graykowski, Byung Il Lee

et al.

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

Published: May 1, 2025

Alzheimer's disease (AD) is initiated by amyloid-beta (Aβ) accumulation in the neocortex; however, cortical layers and neuronal cell types first susceptible to Aβ remain unknown. Using vivo two-photon Ca2+ imaging visual cortex of AD mouse models, we found that layer 5 neurons displayed abnormally prolonged transients before substantial plaque formation. Neuropixels recordings revealed these abnormal were associated with reduced spiking impaired tuning parvalbumin (PV)-positive fast-spiking interneurons (FSIs) 5/6, whereas PV-FSIs superficial remained unaffected. These dysfunctions occurred alongside a deep-layer-specific reduction pentraxin 2 (NPTX2) within excitatory neurons, decreased GluA4 PV-FSIs, fewer synapses onto PV-FSIs. Notably, NPTX2 overexpression increased input 5/6 rectified their activity. Thus, our findings reveal an early selective impairment deep models identify deep-layer as therapeutic targets.

Language: Английский

Citations

0
Rejection of inappropriate synaptic partners in mouse retina mediated by transcellular FLRT2-UNC5 signaling DOI Creative Commons

Cameron L. Prigge,

Mayur Dembla,

Arsha Sharma

et al.

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(20), P. 2080 - 2096.e7

Published: Aug. 8, 2023

Language: Английский

Citations

7
GEARBOCS: An Adeno Associated Virus Tool forIn VivoGene Editing in Astrocytes DOI Creative Commons

Dhanesh Sivadasan Bindu,

Justin T Savage, Nicholas Brose

et al.

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

Published: Jan. 19, 2023

Summary CRISPR/Cas9-based genome engineering enables rapid and precise gene manipulations in the CNS. Here, we developed a non-invasive astrocyte-specific method utilizing single AAV vector, which named GEARBOCS (Gene Editing AstRocytes Based On CRISPR/Cas9 System). We verified GEARBOCS’ specificity to mouse cortical astrocytes demonstrated its utility for three types of manipulations: knockout (KO); tagging (TagIn); reporter knock-in (GeneTrap) strategies. Next, deployed two test cases. First, determined that are necessary source synaptogenic factor Sparcl1 thalamocortical synapse maintenance primary visual cortex. Second, express synaptic vesicle associated Vamp2 protein found it is required maintaining excitatory inhibitory numbers These results show strategy provides fast efficient means study astrocyte biology vivo . Motivation Astrocytes indispensable brain development, function, health. However, molecular tools function have been largely limited genetically modified mice. editing within vector astrocytes. designed optimized this easy-to-use viral tool understand expression, localization

Language: Английский

Citations

4
NeurostimML: A machine learning model for predicting neurostimulation-induced tissue damage DOI Creative Commons
Yi Li, Rebecca A. Frederick, Daniel George

et al.

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

Published: Oct. 21, 2023

Abstract Objective The safe delivery of electrical current to neural tissue depends on many factors, yet previous methods for predicting damage rely only a few stimulation parameters. Here, we report the development machine learning approach that could lead more reliable method stimulation-induced by incorporating additional Approach A literature search was conducted build an initial database response information after stimulation, categorized as either damaging or non-damaging. Subsequently, used ordinal encoding and random forest feature selection, investigated four models classification: Logistic Regression, K-nearest Neighbor, Random Forest, Multilayer Perceptron. Finally, compared results these against accuracy Shannon equation. Main Results We compiled with 387 unique parameter combinations collected from 58 independent studies over period 47 years, 195 (51%) non-damaging 190 (49%) damaging. features selected building our model Forest algorithm were: waveform shape, geometric surface area, pulse width, frequency, amplitude, charge per phase, density, duty cycle, daily duration, number pulses delivered, accumulated charge. equation yielded 63.9% using k value 1.79. In contrast, able robustly predict whether set parameters classified 88.3%. Significance This novel can facilitate informed decision making in selection neuromodulation both research clinical practice. study represents first use prediction damage, lays groundwork neurostimulation driven models.

Language: Английский

Citations

2
Astrocytic LRRK2 Controls Synaptic Connectivity through ERM Phosphorylation DOI Creative Commons
Shiyi Wang, Ryan Baumert, Gabrielle Séjourné

et al.

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

Published: April 10, 2023

SUMMARY Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson’s Disease (PD) is unknown. Here, we investigated impact most common PD-linked mutation leucine-rich repeat kinase 2 ( LRRK2 ) gene (G2019S) on functions astrocytes. We found that both human mouse cortex, G2019S causes morphology deficits enhances phosphorylation ERM proteins (Ezrin, Radixin, Moesin), which are important components perisynaptic processes. Reducing astrocytes restored corrected excitatory deficits. Using an vivo BioID proteomic approach, Ezrin, abundant astrocytic protein, interacts with Autophagy-Related 7 (Atg7), master regulator catabolic The Ezrin/Atg7 interaction inhibited by Ezrin phosphorylation, thus diminished Importantly, Atg7 function required to maintain proper morphology. These studies reveal molecular mechanism could serve therapeutic target PD.

Language: Английский

Citations

0