Biology subjects

Allen, N. J.

Publications and source records attributed to Allen, N. J..

11 recordsLinked to original sources

bioRxiv2025

The antiviral Interferon pathway drives astrocyte aging and motor decline

Aging encompasses low-level inflammation and motor decline. Astrocytes are neuroregulatory glial cells that change in aging, particularly in the cerebellum, which is essential for movement coordination. Regulation and functionality of cerebellar astrocytes in aging is unknown. We show that antiviral type I Interferons (IFN-I) drive motor deficits and regional astrocyte aging. Transcriptomics reveal that cerebellar astrocytes, but not cortical, exhibit an antiviral state that intensifies with age, with increased expression of Stat1. Aged mice display motor deficits similar to humans that improve after peripheral IFN-I receptor neutralization, whereas astrocyte Stat1 induces motor deficits during chronic inflammation in adults. While strong systemic inflammation induces astrocyte antiviral state, in aging, chromatin de-repression of Stat1 and nucleotide sensors in cerebellar astrocytes amplifies local IFN-I signaling. We identify functional interaction between a classical immune pathway and astrocytes, representing an actionable strategy to preserve motor function in aging.

neuroscience↗

bioRxiv2025

Astrocyte SEMA3C reduction improves Rett Syndrome phenotypes

Astrocytes support neuronal function during development through secreted proteins, yet how astrocyte-secreted cues are altered in disease states and contribute to neurodevelopmental disorders remains poorly defined. Rett syndrome (RTT) is a regressive neurodevelopmental disorder characterized by motor, sensory, and cognitive impairments. Here, we identify the class 3 semaphorin SEMA3C as an astrocyte-secreted protein that contributes to RTT pathology. We show that Sema3c expression is elevated in astrocytes in vivo in RTT model mice and find that SEMA3C is sufficient to inhibit cortical neuron dendrite outgrowth. Normalization of astrocyte SEMA3C levels in female RTT model mice rescues dendritic arborization deficits, restores synaptic activity, and improves visual acuity and motor behavior. Mechanistically, both SEMA3C and RTT astrocyte conditioned media inhibit dendrite outgrowth through PLXND1-dependent signaling. Together, these findings identify astrocyte-secreted SEMA3C as a contributor to RTT pathology and highlight SEMA3C and PLXND1 signaling as potential therapeutic targets in neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

CK2 inhibition suppresses glial inflammation in the brain

Neuroinflammation plays a key role in Alzheimers disease (AD) and related neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis. However, glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK22, as a key driver of astrocytic inflammation. CK2 enhances NF-{kappa}B activity by phosphorylating NF-{kappa}B S529 and I{kappa}B S32, promoting pro-inflammatory gene expression. CK2 inhibition via genetic or chemical approaches dampens inflammation, including IL-6 and IL-8 expression in an acute neuroinflammation mouse model. CK22 is upregulated in AD postmortem tissues and patient-derived astrocytes. AD astrocytes exhibit a hyperinflammatory state that can be attenuated by CK2 inhibition. Overexpression of CK22 in cortical organoids mimics AD pathology, whereas CK2 inhibition using the potent, selective, and brain-penetrant probe TAL606 rescues inflammatory markers in transgenic AD mice. These findings position CK2 as a central regulator of neuroinflammation and a promising therapeutic target for AD and related disorders.

neuroscience↗

bioRxiv2024

Astrocyte transcriptomic analysis identifies glypican 5 downregulation as a contributor to synaptic dysfunction in Alzheimer disease models

Synaptic dysfunction is an early feature in Alzheimers disease (AD) and correlates with cognitive decline. Astrocytes are essential regulators of synapses, impacting synapse formation, maturation, elimination and function. To understand if synapse-supportive functions of astrocytes are altered in AD, we used astrocyte BacTRAP mice to generate a comprehensive dataset of hippocampal astrocyte transcriptional alterations in two mouse models of Alzheimers pathology (APPswe/PS1dE9 and Tau P301S), characterizing sex and age-dependent changes. We found that astrocytes from both models downregulate genes important for synapse regulation and function such as the synapse-maturation factor Glypican 5. This transcriptional signature is shared with human post-mortem AD patients. Manipulating a key component of this signature by in vivo overexpression of Glypican 5 in astrocytes is sufficient to prevent early synaptic dysfunction and improve spatial learning in APPswe/PS1dE9 mice. These findings open new avenues to target astrocytic factors to mitigate AD synaptic dysfunction.

neuroscience↗

bioRxiv2024

Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, and found this lessens audiogenic seizure severity in FXS mice. To ask how this occurs on a molecular level, we performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted proteins in FXS astrocytes, with these alterations no longer present when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses present in FXS auditory cortex. Thus, astrocytes contribute to FXS molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.

neuroscience↗

bioRxiv2024

Astrocyte CCN1 stabilizes neural circuits in the adult brain

Neural circuits in many brain regions are refined by experience. Sensory circuits support higher plasticity at younger ages during critical periods - times of circuit refinement and maturation - and limit plasticity in adulthood for circuit stability. The mechanisms underlying these differing plasticity levels and how they serve to maintain and stabilize the properties of sensory circuits remain largely unclear. By combining a transcriptomic approach with ex vivo electrophysiology and in vivo imaging techniques, we identify that astrocytes release cellular communication network factor 1 (CCN1) to maintain synapse and circuit stability in the visual cortex. By overexpressing CCN1 in critical period astrocytes, we find that it promotes the maturation of inhibitory circuits and limits ocular dominance plasticity. Conversely, by knocking out astrocyte CCN1 in adults, binocular circuits are destabilized. These studies establish CCN1 as a novel astrocyte-secreted factor that stabilizes neuronal circuits. Moreover, they demonstrate that the composition and properties of sensory circuits require ongoing maintenance in adulthood, and that these maintenance cues are provided by astrocytes.

neuroscience↗

bioRxiv2023

Dysregulation of astrocyte-secreted pleiotrophin contributes to neuronal structural and functional phenotypes in Down Syndrome

Neuronal dendrite patterning and synapse formation are tightly regulated during development to promote proper connectivity. Astrocyte-secreted proteins act as guidance and pro-synaptogenic factors during development, but little is known about how astrocytes may contribute to neurodevelopmental disorders. Here we identify down-regulation of the astrocyte-secreted molecule pleiotrophin as a major contributor to neuronal morphological alterations in the Ts65Dn mouse model of Down Syndrome. We find overlapping deficits in neuronal dendrites, spines and intracortical synapses in Ts65Dn mutant and pleiotrophin knockout mice. By targeting pleiotrophin overexpression to astrocytes in adult Ts65Dn mutant mice in vivo, we show that pleiotrophin can rescue dendrite morphology and spine density and increase excitatory synapse number. We further demonstrate functional improvements in behavior. Our findings identify pleiotrophin as a molecule that can be used in Down Syndrome to promote proper circuit connectivity, importantly at later stages of development after typical periods of circuit refinement have completed.

neuroscience↗

bioRxiv2023

Astrocyte glypican 5 regulates synapse maturation and stabilization

The maturation and stabilization of appropriate synaptic connections is a vital step in the development of neuronal circuits, however the molecular signals underlying these processes are not fully understood. We show that astrocytes, through production of glypican 5 (GPC5), are required for maturation and refinement of synapses in the developing mouse cortex. In the absence of astrocyte GPC5 thalamocortical synapses in the visual cortex show structural immaturity during the critical period, including smaller presynaptic terminals, decreased postsynaptic density area, and presence of more postsynaptic partners at multisynaptic connections. This structural immaturity is accompanied by a delay in developmental incorporation of GLUA2-containing calcium impermeable AMPARs at intracortical synapses. The functional impact of this is that mice lacking astrocyte GPC5 exhibit increased levels of ocular dominance plasticity in adulthood. This shows astrocyte GPC5 is necessary for maturation and stabilization of synaptic connections in typical development, with implications for understanding disorders with altered synaptic function, including Alzheimers disease, where GPC5 levels are altered.

neuroscience↗

bioRxiv2020

Activity-Dependent Modulation of Synapse-Regulating Genes in Astrocytes

Astrocytes regulate the formation and function of neuronal synapses via multiple signals, however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually-evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development are also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, identifying astrocytes as a target to manipulate in neurodevelopmental disorders.

neuroscience↗

bioRxiv2020

Astrocyte-secreted chordin-like 1 regulates spine density after ischemic stroke

Ischemic stroke occurs when the brain is deprived of blood flow, preventing cells from receiving nutrients necessary to perform basic vital functions. In the peri-infarct area neurons undergo an acute loss of dendritic spines along with morphological alterations, which ultimately modify synaptic plasticity and determine neuronal survival. Astrocytes have been shown to play protective or detrimental roles in neuronal survival post-stroke, depending on the specific stage, yet we lack a clear understanding of the underlying mechanisms triggered at these different time points. Recently chordin-like 1 (Chrdl1) was identified as an astrocyte-secreted protein that promotes synaptic maturation and limits experience-dependent plasticity in the mouse visual cortex, leading us to ask if Chrdl1 regulates spine density and recovery from stroke. Using photothrombosis to model ischemic stroke, we studied Chrdl1 KO mice during the acute and subacute phases post-stroke (1 and 7 days after injury, respectively) to assess the potential of Chrdl1 to regulate spine density, glial reactivity and injury volume, characteristics that are involved in functional recovery after ischemia. We find that the absence of Chrdl1 prevents ischemia-induced spine loss in the peri-infarct area, a feature that indicates an important role of astrocytes in recovery from ischemic stroke.

neuroscience↗

bioRxiv2020

Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

Astrocytes negatively impact neuronal development in many neurodevelopmental disorders (NDs), however how they do this, and if mechanisms are shared across disorders, is not known. We developed an in vitro system to ask how astrocyte protein secretion and gene expression change in three genetic NDs. We identified disorder specific changes, and changes common to all disorders. ND astrocytes increase release of Igfbp2, a secreted inhibitor of IGF. IGF rescues neuronal deficits in many NDs, and we found blocking Igfbp2 partially rescues inhibitory effects of Rett Syndrome astrocytes, suggesting increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified increased BMP signaling in ND astrocytes is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X Syndrome astrocytes reverses inhibitory effects on neurite outgrowth. We provide a resource of astrocyte secreted proteins in health and NDs, and identify novel targets for intervention in diverse NDs.

neuroscience↗