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

Astrocyte-secreted neurocan controls inhibitory synapse formation and function DOI Creative Commons
Dolores Irala, Shiyi Wang, Kristina Sakers

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(10), P. 1657 - 1675.e10

Published: April 3, 2024

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. Several astrocyte-secreted synaptogenic proteins controlling excitatory synapse development were identified; however, those that induce inhibitory synaptogenesis remain elusive. Here, we identify neurocan as an protein. After secretion from astrocytes, is cleaved into N- C-terminal fragments. We found these fragments have distinct localizations in extracellular matrix. The fragment localizes to controls cortical function. Neurocan knockout mice lacking whole protein or only its domain reduced numbers Through super-resolution microscopy, vivo proximity labeling TurboID, astrocyte-specific rescue approaches, discovered somatostatin-positive regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific mammalian brain.

Language: Английский

Citations

24
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
Neuron Derived Cytokine Interleukin-34 Controls Developmental Microglia Function DOI Creative Commons
Benjamin A. Devlin, Dang M. Nguyen,

Gabriel Grullon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 10, 2024

Neuron-microglia interactions dictate the development of neuronal circuits in brain. However, factors that support and broadly regulate these processes across developmental stages are largely unknown. Here, we find IL34, a neuron-derived cytokine, is upregulated plays critical role supporting maintaining neuroprotective, mature microglia anterior cingulate cortex (ACC) mice. We show IL34 mRNA protein neurons second week postnatal life this increase coincides with increases number expression mature, homeostatic markers, e.g., TMEM119. also found higher more active neurons, excitatory (compared to inhibitory) neurons. Genetic KO prevents functional maturation results an anxiolytic phenotype mice by adulthood. Acute, low dose blocking at day (P)15 decreased microglial TMEM119 increased aberrant phagocytosis thalamocortical synapses within ACC. In contrast, viral overexpression early (P1-P8) caused prevented during appropriate neurodevelopmental refinement window. Taken together, findings establish as key regulator neuron-microglia crosstalk brain development, controlling both synapse engulfment.

Language: Английский

Citations

3
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
NeurostimML: a machine learning model for predicting neurostimulation-induced tissue damage DOI Creative Commons
Yi Li, Rebecca A. Frederick,

Daniel George

et al.

Journal of Neural Engineering, Journal Year: 2024, Volume and Issue: 21(3), P. 036054 - 036054

Published: June 1, 2024

. 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

Language: Английский

Citations

2
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
Astrocytic thrombospondins 1 and 2 are required for cortical synapse development controlling instrumental performance DOI Open Access
Oluwadamilola O. Lawal, Francesco Paolo Ulloa Severino, Shiyi Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 4, 2024

Abstract During development, controlled synaptogenesis is required to form functioning neural circuits that underlie cognition and behavior. Astrocytes, a major glial-cell type in the central nervous system (CNS), promote synapse formation by secreting synaptogenic proteins. Thrombospondins 1 2 (TSP1/2), which act through their neuronal receptor α2δ-1, are for proper intracortical excitatory synaptogenesis. In adult brain, loss of α2δ-1 impairs training-induced anterior cingulate cortex (ACC), this impairment leads increased effort-exertion during high-effort tasks. Here, we tested whether TSP1 TSP2 controlling effort operant conditioning using lever press food reward training mice. Surprisingly, found constitutive TSP1/2 significantly reduced pressing performance when was increased, phenotype opposite loss. Loss number brains. However, ACC knockout mice, there still synaptogenesis, likely upregulation TSP4, TSP isoform also synaptogenic. Unexpectedly, significant increase inhibitory function eliminated after training. Finally, astrocyte-specific ablation developing but not astrocytes sufficient reduce Taken together, our study highlights importance developmental astrocyte-derived cues establishing control adults.

Language: Английский

Citations

1
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
GEARBOCS: An Adeno Associated Virus Tool for In Vivo Gene Editing in Astrocytes DOI Open Access

Dhanesh Sivadasan Bindu,

Justin T Savage, Nicholas Brose

et al.

Published: Dec. 11, 2024

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 .

Language: Английский

Citations

0
GEARBOCS: An Adeno Associated Virus Tool for In Vivo Gene Editing in Astrocytes DOI Open Access

Dhanesh Sivadasan Bindu,

Justin T Savage, Nicholas Brose

et al.

Published: Dec. 11, 2024

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 .

Language: Английский

Citations

0