Biology subjects

Relvas, J. B.

Publications and source records attributed to Relvas, J. B..

11 recordsLinked to original sources

bioRxiv2024

Increasing the vitamin C transporter SVCT2 in microglia improves synaptic plasticity and restrains memory impairments in Alzheimer's disease models

Alzheimers Disease (AD) is characterized by progressive cognitive decline and synaptic dysfunction, often associated with amyloid-beta accumulation and microglial alterations. Here, we investigate the role of the Sodium-dependent Vitamin C Transporter 2 (SVCT2) in microglia to modulate AD-like pathology in mice. Using a combination of RNA sequencing, advanced quantitative proteomics, electrophysiology, behavioral tests, high-throughput imaging, and microglial viral gene delivery, we explore the interplay between SVCT2 expression in microglia, amyloid-beta load, synaptic proteome changes, and synaptic plasticity. Our results demonstrate that SVCT2 expression in microglia decreases with age in the 5xFAD mice, correlating with memory deficits and alterations in synaptic mitochondrial proteome. Importantly, overexpression of SVCT2 in microglia leads to enhanced clearance of amyloid plaques and reconfiguration of the mitochondrial proteome landscape in the synapses, improving synaptic long-term plasticity (LTP) and memory performance. Our findings underscore the SVCT2 overexpression in microglia as a potent strategy to simultaneously decrease amyloid pathology and enhance synaptic plasticity and memory performance, offering new avenues for therapeutic interventions in AD.

neuroscience↗

bioRxiv2024

Neuronal ARHGAP8 controls synapse structure and AMPA receptor-mediated synaptic transmission

The aberrant formation and function of neuronal synapses are recognized as major phenotypes in many cases of neurodevelopmental (NDDs) and -psychiatric disorders (NPDs). A growing body of research has identified an expanding number of susceptibility genes encoding proteins with synaptic function. Here, we present the first brain-focused characterization of a potential new susceptibility gene, ARHAGP8, which encodes a Rho GTPase activating protein (RhoGAP). Accumulating evidence suggests that ARHGAP8 plays a pivotal role in the pathogenesis of NPDs/NDDs. We provide the first evidence for ARHGAP8 as a novel player at excitatory synapses, with its synaptic localisation linked to the presence of the developmentally important NMDA receptor subunit GluN2B. By increasing ARHGAP8 levels in hippocampal neurons to mimic the copy number variant found in a subset of patients, we observed reductions in dendritic complexity and spine volume, accompanied by a significant decrease in synaptic AMPA receptor-mediated transmission. These results suggest that ARHGAP8 plays a role in shaping the morphology and function of excitatory synapses, and prompt further investigation of ARHGAP8 as a candidate gene in NDDs/NPDs.

neuroscience↗

bioRxiv2023

Unexpected Kif4a functions in adult regeneration encompass a dual role in neurons and in proliferative repair Schwann cells.

Contrary to the adult central nervous system (CNS), the peripheral nervous system (PNS) has an intrinsic ability to regenerate that, among others, passes by expressing regeneration-associated genes such as kinesin family members. We here show that Kinesin family motor protein 4a (KIF4A), associated to neurodevelopmental disorders and thought for long to be only embryonically expressed, is highly abundant in axons and Schwann cells of adult rat CNS and rat and human PNS. Moreover, Kif4a is up-regulated in injured PNS neurons, being detected in their nuclei and regrowing axons, consistent with its functions as a chromokinesin and in the axonal transport of e.g. {beta}1-integrin and L1CAM. Interestingly, Kif4a is also highly up-regulated in Schwann cells transdifferentiating into a proliferative repair phenotype at the injured distal nerve stumps. A role for Kif4a in cultured Schwann cells proliferation was confirmed, with Kif4a mRNA expression being [~]6-fold higher in proliferating versus growth-arrested Schwann cells, and Kif4a knockdown impairing Schwann cells proliferation. To our knowledge, this is the first description of KIF4A expression in adult nervous systems, up-regulation in neuroregeneration and pro-neuroregenerative roles, including promoting Schwann cells proliferation. KIF4A dual role in axonal regeneration, through neurons and glia, places as an attractive target for future neuroregeneration therapies.

neuroscience↗

bioRxiv2023

Prefrontal cortex proteomic alteration after social instability stress in adolescents rats

Early life stress can have significant effects on the developing brain and lead to changes in the structure and function of brain regions involved in stress regulation, emotion and cognitive control. Here, we used the social instability stress (SIS) protocol to understand the impact of social stress during mild (PND30) and late (PND45) adolescence. Our results revealed that SIS can compromise the dominance-subordination coping strategy but does not affect social recognition and motivation in rats. Moreover, SIS can lead to subtle modifications at the molecular level that hamper normal development of the prefrontal cortex in a sex- and age-dependent manner. Understanding the impact of early life stress on brain organization is crucial for developing effective prevention and intervention strategies. By identifying those who are most vulnerable to the effects of stress and providing targeted support and resources, it may be possible to mitigate the negative consequences of early adversity and promote healthy brain development.

neuroscience↗

bioRxiv2021

Control of cortical cytoskeleton-membrane interaction by RhoA regulates peripheral nerve myelination

Bidirectional transmission of mechanical and biochemical signals is integral to cell-environment communication and underlies the function of Schwann cells, the myelinating glia of the peripheral nervous system. As major integrators of "outside-in" signaling, Rho GTPases link actin cytoskeleton dynamics with cellular architecture to regulate adhesion and cell deformation. Using Schwann cell-specific gene inactivation, we discovered that RhoA promotes the initiation of myelination, axonal wrapping and axial spreading of Schwann cells, and is later required to restrict myelin growth in peripheral nerves. These effects are mediated by modulation of actomyosin contractility, actin dynamics and cortical actin-membrane attachment, which collectively couple tensional forces to intracellular signaling that regulate axon-Schwann cell interaction and myelin synthesis. This work establishes RhoA as an intrinsic regulator of a biomechanical response that controls the switch of Schwann cells towards the myelinating and the homeostatic states.

neuroscience↗

bioRxiv2021

Microglia remodel the synaptic signaling required for context-dependent cognitive performance

Microglial homeostatic functions are fundamental to regulate the central nervous system microenvironment. We use conditional cell-specific gene targeting, RNA-seq profiling, high-throughput proteomics, phosphoproteomics, systems biology, and animal behavior to report a critical role for the RhoGTPase Rac1 in regulating adult microglia physiology. Ablation of Rac1 in adult microglia impaired their ability to sense and interpret the brain microenvironment and affected their capacity to communicate with synapses to drive cognitive performance, both at the steady-state and during experience-dependent plasticity. Overall, our results reveal a novel and central role for Rac1 as a regulator of microglia homeostasis and a molecular driver of the microglia-synapse crosstalk required for context-dependent sociability and learning related to memory.

neuroscience↗

bioRxiv2021

The proteome of remyelination is different from that of developmental myelination

Loss of myelin underlies the pathology of several neurological disorders of diverse etiology. CNS remyelination by adult oligodendrocyte progenitor cells (OPCs) can occur but it differs from developmental myelination carried out by neonatal OPCs. We asked whether the myelin proteome of remyelinated regions is changed. We compared the myelin proteome formed during development to the remyelination proteome attained after lysolecithin-induced demyelination in the mouse spinal cord. Mass-spectrometry analysis of iTRAQ labelled myelin protein lysates showed that the proteome of remyelination is different from that of developmental myelination, leading to profound changes in myelin protein content. Aside from known mediators of oligodendrocyte differentiation, we found proteome alterations included modulators of metabolism, cell signaling and actin cytoskeleton dynamics. Downregulating one candidate (FSCN1/Fascin1) was sufficient to partially hamper oligodendrocytes in-vitro. In summary, we identify the difference in the proteome of remyelinating oligodendrocytes as a novel potential contributor to the pathophysiology of demyelinating disorders, thus providing new potential therapeutic targets for future studies.

neuroscience↗

bioRxiv2021

Astrocyte-derived TNF and glutamate critically modulate microglia reactivity by methamphetamine

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation that contributes to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders linked to cognitive impairment and neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in human Meth abusers), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a manner dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production or suppressing astrocytic calcium mobilization prevented microglia reactivity and abolished the behavioral phenotype elicited by Meth exposure. Overall, our data indicate that glial crosstalk is critical to relay behavioral alterations caused by acute Meth exposure. One Sentence SummaryGlial crosstalk under methamphetamine exposure

neuroscience↗

bioRxiv2020

The Pebble/Rho1/Anillin pathway controls polyploidization and axonal wrapping activity in the glial cells of the Drosophila eye

During development glial cell are crucially important for the establishment of neuronal networks. Proliferation and migration of glial cells can be modulated by neurons, and in turn glial cells can differentiate to assume key roles such as axonal wrapping and targeting. To explore the roles of actin cytoskeletal rearrangements in glial cells, we studied the function of Rho1 in Drosophila developing visual system. We show that the Pebble (RhoGEF)/Rho1/Anillin pathway is required for glia proliferation and to prevent the formation of large polyploid perineurial glial cells, which can still migrate into the eye disc if generated. Surprisingly, this Rho1 pathway is not necessary to establish the total glial membrane area or for the differentiation of the polyploid perineurial cells. The resulting polyploid wrapping glial cells are able to initiate wrapping of axons in the basal eye disc, however the arrangement and density of glia nuclei and membrane processes in the optic stalk are altered and the ensheathing of the photoreceptor axonal fascicles is reduced.

developmental biology↗

bioRxiv2019

Alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior

Alcohol use adversely impacts the life of millions of people worldwide. Deficits in synaptic transmission and in microglial function are common findings in human alcohol users and in animal models of alcohol intoxication. Here, we show that alcohol intake over ten consecutive days resulted in substantial loss of excitatory synapse in the prefrontal cortex, a consequence of aberrant synaptic pruning, which led to increased anxiety-like behavior. Mechanistically, these effects of alcohol intake were mediated by a detrimental increase of microglia engulfment capacity via Src-dependent activation of NFkB and consequent TNF production. Accordingly, pharmacological blockade of Src activation or TNF production by microglia, genetic ablation of TNF, or diphtheria toxin-mediated conditional ablation of microglia attenuated aberrant synaptic pruning preventing excitatory synapse loss and anxiety-like behavior. Overall, our data suggest that aberrant pruning of excitatory synapses by microglia might disrupt synaptic transmission during alcohol use.

neuroscience↗

bioRxiv2017

Genetic ablation of RhoA in adult microglia causes synapse and neuronal loss

Nervous tissue homeostasis requires regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation producing a neurological phenotype (including synapse and neuron loss, impairment of LTP, formation of {beta}-amyloid plaques and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated Tnf production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also found that the Rhoa/Src signaling pathway was disrupted in microglia of the APP/PS1 mouse model of Alzheimers disease and that low doses of A{beta} oligomers triggered microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.

neuroscience↗