Biology subjects

Saghatelyan, A.

Publications and source records attributed to Saghatelyan, A..

7 recordsLinked to original sources

bioRxiv2026

Cilia beating of ependymal cells regulates adult neural stem cell quiescence via mechanical forces mediated by PKD1/2-TRPM3

In many tissues stem cells are located lining a fluid-filled volume and their neighboring niche cells include cells with beating cilia. However, the role of mechanical forces created by cilia beating on stem cells remains elusive. We developed an approach to transiently inhibit the cilia beating of ependymal cells (EC) lining the forebrain ventricle by injecting magnetic beads-coupled antibodies targeting EC cilia and then applying a magnetic field. We show that EC cilia beating enforces neural stem cells (NSCs) quiescence through mechano-sensitive PKD1/2- and TRPM3-mediated Ca2+ transients. Only a few hours of EC cilia beating inhibition triggered NSC activation in vivo. CRISPR-Cas9-mediated deletion of TRPM3 or PKD1/2 in NSCs phenocopied the effect of EC cilia beating inhibition, while TRPM3 pharmacological activation rescued NSC quiescence in the absence of cilia beating. Our data reveal a novel regulator of stem cells exposed to fluids via the mechanical forces mediated by cilia beating.

neuroscience↗

bioRxiv2025

Purinergic receptor activation rectifies autism-associated endothelial dysfunction

Early cerebrovascular alterations affect brain maturation by impacting trophic support and energy supply. Recent evidence in a 16p11.2 deletion mouse model of autism spectrum disorder (ASD) revealed brain endothelial abnormalities postnatally. Yet, the endothelial alterations eliciting these changes remain unknown. Isolation of brain endothelial cells (ECs) from 14-day old male 16p11.2-deficient and wild-type mice revealed that 16p11.2 deletion-induced endothelial dysfunction is linked to a bioenergetic failure, with reduced intracellular ATP. Intra- or extra-cellular ATP supplementation rescued the function of 16p11.2-deficient ECs in vitro via P2 purinergic receptor activation, specifically P2Y2 receptors. Activating P2Y2 receptors restored cerebrovascular reactivity in 16p11.2-deficient parenchymal arterioles ex vivo and rescued 16p11.2 deletion-associated mouse behaviors. Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a possible therapeutic avenue for ASD.

cell biology↗

bioRxiv2023

Distinct forms of structural plasticity of adult-born interneuron spines induced by different odor learning paradigms

During development and in adulthood the morpho-functional properties of neural networks constantly adapt in response to environmental stimuli and learned experiences. One of the processes that allows neuronal networks to be constantly reshaped is synaptic plasticity, which is induced in response to sensory experience and learning. Synaptic plasticity allows for the formation/elimination of synaptic connections as well as the strengthening of pre-existing ones. The olfactory system is particularly prone to constant morpho-functional reshaping of neural networks and synaptic rewiring throughout the lifespan of an animal, mainly because of the presence of continuous neurogenesis in the olfactory bulb (OB). This constant synaptic rewiring brought by adult-born neurons is modulated by the level of odor-induced activity and olfactory learning. It remains, however, unclear whether the complexity of distinct odor-induced learning paradigms and sensory stimulation induces different forms of structural plasticity. In the present study, we developed an analytical pipeline to perform 3D reconstructions of spines from confocal images followed by clustering of reconstructed spines based on different morphometric features and in relationship with different sensory stimuli and learning paradigms. We show that while sensory deprivation decreased the overall density of adult-born neurons in the OB without any noticeable changes in the morphometric properties of these spines, simple and complex odor learning paradigms triggered distinct forms of structural plasticity. A simple odor learning task affected the morphometric properties of the spines without any changes in spine density, whereas a complex odor learning task induced changes in spine density, without substantial changes in the morphology of the spines. Our work reveals the vast panoply of distinct forms of synaptic plasticity of adult-born neurons in the OB tailored to the complexity of odor-learning paradigms and sensory inputs.

neuroscience↗

bioRxiv2021

SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection

COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via still elusive mechanisms. SARS-CoV-2 infects host cells by binding to angiotensin-converting enzyme 2 (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury in COVID-19. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 expression in human brain vascular pericytes is highly dynamic and is increased upon S protein stimulation. Pericytes exposed to S protein underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely -smooth muscle actin (-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-{kappa}B) signalling pathway, which was potentiated by hypoxia, a condition associated to vascular comorbidities, which exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 (IL-8), IL-18, macrophage migration inhibitory factor (MIF), and stromal cell-derived factor-1 (SDF-1). Finally, we found that S protein could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19. Our data demonstrate that the released S protein is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury in absence of a productive viral infection. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.

neuroscience↗

bioRxiv2020

Autophagy is required for midbrain dopaminergic axon development and their responsiveness to guidance cues

Mesodiencephalic dopamine (mDA) neurons play a wide range of brain functions. Distinct subtypes of mDA neurons regulate these functions but the molecular mechanisms that drive the mDA circuit formation are largely unknown. Here we show that autophagy, the main recycling cellular pathway, is present in the growth cones of developing mDA neurons and its level changes dynamically in response to guidance cues. To characterize the role of autophagy in mDA axon growth/guidance, we knocked-out (KO) essential autophagy genes (Atg12, Atg5) in mice mDA neurons. Autophagy deficient mDA axons exhibit axonal swellings and decreased branching both in vitro and in vivo, likely due to aberrant microtubule looping. Strikingly, deletion of autophagy-related genes, blunted completely the response of mDA neurons to chemo-repulsive and chemo-attractive guidance cues. Our data demonstrate that autophagy plays a central role in regulating mDA neurons development, orchestrating axonal growth and guidance.

neuroscience↗

bioRxiv2020

The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migration in vivo

Cell migration is a dynamic process that entails extensive protein synthesis and recycling, structural remodeling, and a considerable bioenergetic demand. Autophagy is one of the pathways that maintain cellular homeostasis. Time-lapse imaging of autophagosomes and ATP/ADP levels in migrating cells in the rostral migratory stream of mice revealed that decrease in ATP levels force cells into the stationary phase and induce autophagy. Genetic impairment of autophagy in neuroblasts using either inducible conditional mice or CRISPR/Cas9 gene editing decreased cell migration due to the longer duration of the stationary phase. Autophagy is modulated in response to migration-promoting and inhibiting molecular cues and is required for the recycling of focal adhesions. Our results show that autophagy and energy consumption act in concert in migrating cells to dynamically regulate the pace and periodicity of the migratory and stationary phases in order to sustain neuronal migration. HighlightsO_LIADP levels dynamically change during cell migration C_LIO_LIA decrease in ATP levels leads to cell pausing and autophagy induction via AMPK C_LIO_LIAutophagy is required to sustain neuronal migration by recycling focal adhesions C_LIO_LIAutophagy level is dynamically modulated by migration-promoting and inhibiting cues C_LI

neuroscience↗

bioRxiv2020

Inhibition of mTOR during a postnatal sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1.

Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear. Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

neuroscience↗