A tripartite circRNA/mRNA/miRNA interaction regulates glutamatergic signaling in the mouse brain.

Functional studies of circular RNAs (circRNAs) began quite recently, and few data exist on their function in vivo. Here, we have generated a knockout (KO) mouse model to study circDlc1(2), a circRNA highly expressed in the prefrontal cortex and striatum. The loss of circDlc1(2) led to the upregulation of glutamatergic-response-associated genes in the striatal tissue, enhanced excitatory synaptic transmission in neuronal cultures, and hyperactivity and increased stereotypies in mice.

Microglial Modulation of Synaptic Maturation, Activity, and Plasticity.

Microglia, which are the resident immune cells of the CNS, also have important functions in physiological conditions. In this chapter, we review the experimental evidence that microglia modulate neuronal and synaptic activity during normal development and in adults. We show that microglia can regulate the maturation and function of both inhibitory and excitatory synapses that can be stimulated or repressed.

Microglia at the Tripartite Synapse during Postnatal Development: Implications for Autism Spectrum Disorders and Schizophrenia.

Synapses are the fundamental structures of neural circuits that control brain functions and behavioral and cognitive processes. Synapses undergo formation, maturation, and elimination mainly during postnatal development via a complex interplay with neighboring astrocytes and microglia that, by shaping neural connectivity, may have a crucial role in the strengthening and weakening of synaptic functions, that is, the functional plasticity of synapses. Indeed, an increasing number of studies have unveiled the roles of microglia and astrocytes in synapse formation, maturation, and elimination as well as in regulating synaptic function.

Phospholipid scramblase Xkr8 is required for developmental axon pruning via phosphatidylserine exposure.

The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players in the phagocytic elimination of neuronal synapses and projections. Recently, phosphatidylserine has been identified as neuronal "eat-me" signal that guides elimination of unnecessary input sources, but the associated transduction systems involved in such pruning are yet to be described.

Microglia reactivity entails microtubule remodeling from acentrosomal to centrosomal arrays.

Microglia reactivity entails a large-scale remodeling of cellular geometry, but the behavior of the microtubule cytoskeleton during these changes remains unexplored. Here we show that activated microglia provide an example of microtubule reorganization from a non-centrosomal array of parallel and stable microtubules to a radial array of more dynamic microtubules. While in the homeostatic state, microglia nucleate microtubules at Golgi outposts, and activating signaling induces recruitment of nucleating material nearby the centrosome, a process inhibited by microtubule stabilization.

Human iPSC-Derived Cortical Neurons Display Homeostatic Plasticity.

Maintaining the excitability of neurons and circuits is fundamental for healthy brain functions. The global compensatory increase in excitatory synaptic strength, in response to decreased activity, is one of the main homeostatic mechanisms responsible for such regulation. This type of plasticity has been extensively characterized in rodents in vivo and in vitro, but few data exist on human neurons maturation.

What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior.

Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain.

Microglia states and nomenclature: A field at its crossroads.

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions.

Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells.

The complexity of the microenvironment effects on cell response, show accumulating evidence that glioblastoma (GBM) migration and invasiveness are influenced by the mechanical rigidity of their surroundings. The epithelial-mesenchymal transition (EMT) is a well-recognized driving force of the invasive behavior of cancer. However, the primary mechanisms of EMT initiation and progression remain unclear.

Antibiotics Treatment Modulates Microglia-Synapses Interaction.

'Dysbiosis' of the adult gut microbiota, in response to challenges such as infection, altered diet, stress, and antibiotics treatment has been recently linked to pathological alteration of brain function and behavior. Moreover, gut microbiota composition constantly controls microglia maturation, as revealed by morphological observations and gene expression analysis. However, it is unclear whether microglia functional properties and crosstalk with neurons, known to shape and modulate synaptic development and function, are influenced by the gut microbiota.

Microglia control glutamatergic synapses in the adult mouse hippocampus.

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice.

Microglia modulate hippocampal synaptic transmission and sleep duration along the light/dark cycle.

Microglia, the brain's resident macrophages, actively contribute to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor-1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice.

Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice.

Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes.

Resilience to anhedonia-passive coping induced by early life experience is linked to a long-lasting reduction of I current in VTA dopaminergic neurons.

Exposure to aversive events during sensitive developmental periods can affect the preferential coping strategy adopted by individuals later in life, leading to either stress-related psychiatric disorders, including depression, or to well-adaptation to future adversity and sources of stress, a behavior phenotype termed "resilience". We have previously shown that interfering with the development of mother-pups bond with the Repeated Cross Fostering (RCF) stress protocol can induce resilience to depression-like phenotype in adult C57BL/6J female mice. Here, we used patch-clamp recording in midbrain slice combined with both and pharmacology to test our hypothesis of a link between electrophysiological modifications of dopaminergic neurons in the intermediate Ventral Tegmental Area (VTA) of RCF animals and behavioral resilience.

Dimethyl Fumarate Reduces Microglia Functional Response to Tissue Damage and Favors Brain Iron Homeostasis.

Dimethyl fumarate (DMF) is the only available approved drug for first line treatment of multiple sclerosis (MS), a lethal condition impairing central nervous system (CNS). To date, however, little is known of its mechanisms of action. Only recently, it has been suggested that DMF exerts neuroprotective effects acting as an immunomodulator and that it may alter the activation state of microglia cells, crucial in MS pathogenesis.

Neuroinflammatory Processes, A1 Astrocyte Activation and Protein Aggregation in the Retina of Alzheimer's Disease Patients, Possible Biomarkers for Early Diagnosis.

Alzheimer's disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid-beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic is among the main causes of pharmacological therapy and clinical trials failure; therefore, the actual challenge is to define new biomarkers and non-invasive technologies to measure neuropathological changes at pre-symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non-invasive rapid detection of AD biomarkers.

Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence.

We recently introduced an animal model to study incubation of drug craving after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Here we studied the role of the nucleus accumbens (NAc) in this model. We trained rats to self-administer a palatable solution (sucrose 1% + maltodextrin 1%, 6 h/day, 6 days) and methamphetamine (6 h/day, 12 days).

Microglia-neuron crosstalk: Signaling mechanism and control of synaptic transmission.

The continuous crosstalk between microglia and neurons is required for microglia housekeeping functions and contributes to brain homeostasis. Through these exchanges, microglia take part in crucial brain functions, including development and plasticity. The alteration of neuron-microglia communication contributes to brain disease states with consequences, ranging from synaptic function to neuronal survival.

Mechanical Durotactic Environment Enhances Specific Glioblastoma Cell Responses.

: A hallmark of glioblastoma is represented by their ability to widely disperse throughout the brain parenchyma. The importance of developing new anti-migratory targets is critical to reduce recurrence and improve therapeutic efficacy. : Polydimethylsiloxane substrates, either mechanically uniform or presenting durotactic cues, were fabricated to assess GBM cell morphological and dynamical response with and without pharmacological inhibition of NNMII contractility, of its upstream regulator ROCK and actin polymerization.

Time-lapse Whole-field Fluorescence Imaging of Microglia ProcessesMotility in Acute Mouse Hippocampal Slices and Analysis.

Microglia are the resident immune cells of the central nervous system (CNS). In the last year, the improvements in the transgenic mouse technologies and imaging techniques have shed light on microglia functions under physiological conditions. Microglia continuously scan the brain parenchyma with their highly motile processes, maintaining tissue homeostasis and participating in neuronal circuits refinement.