Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

Aberrant iPSC-derived human astrocytes in Alzheimer's disease

The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically-defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including; glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles, and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neuronal intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell-autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD

CSF tau is associated with impaired cortical plasticity, cognitive decline and astrocyte survival only in APOE4-positive Alzheimer's disease

In Alzheimer's disease (AD) patients, apopoliprotein (APOE) polymorphism is the main genetic factor associated with more aggressive clinical course. However, the interaction between cerebrospinal fluid (CSF) tau protein levels and APOE genotype has been scarcely investigated. A possible key mechanism invokes the dysfunction of synaptic plasticity. We investigated how CSF tau interacts with APOE genotype in AD patients. We firstly explored whether CSF tau levels and APOE genotype influence disease progression and long-term potentiation (LTP)-like cortical plasticity as measured by transcranial magnetic stimulation (TMS) in AD patients. Then, we incubated normal human astrocytes (NHAs) with CSF collected from sub-groups of AD patients to determine whether APOE genotype and CSF biomarkers influence astrocytes survival. LTP-like cortical plasticity differed between AD patients with apolipoprotein E4 (APOE4) and apolipoprotein E3 (APOE3) genotype. Higher CSF tau levels were associated with more impaired LTP-like cortical plasticity and faster disease progression in AD patients with APOE4 but not APOE3 genotype. Apoptotic activity was higher when cells were incubated with CSF from AD patients with APOE4 and high tau levels. CSF tau is detrimental on cortical plasticity, disease progression and astrocyte survival only when associated with APOE4 genotype. This is relevant for new therapeutic approaches targeting tau

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions

Neuron-glial Interactions

Although lagging behind classical computational neuroscience, theoretical and computational approaches are beginning to emerge to characterize different aspects of neuron-glial interactions. This chapter aims to provide essential knowledge on neuron-glial interactions in the mammalian brain, leveraging on computational studies that focus on structure (anatomy) and function (physiology) of such interactions in the healthy brain. Although our understanding of the need of neuron-glial interactions in the brain is still at its infancy, being mostly based on predictions that await for experimental validation, simple general modeling arguments borrowed from control theory are introduced to support the importance of including such interactions in traditional neuron-based modeling paradigms.Junior Leader Fellowship Program by “la Caixa” Banking Foundation (LCF/BQ/LI18/11630006

Roles of glial cells in synapse development

Brain function relies on communication among neurons via highly specialized contacts, the synapses, and synaptic dysfunction lies at the heart of age-, disease-, and injury-induced defects of the nervous system. For these reasons, the formation—and repair—of synaptic connections is a major focus of neuroscience research. In this review, I summarize recent evidence that synapse development is not a cell-autonomous process and that its distinct phases depend on assistance from the so-called glial cells. The results supporting this view concern synapses in the central nervous system as well as neuromuscular junctions and originate from experimental models ranging from cell cultures to living flies, worms, and mice. Peeking at the future, I will highlight recent technical advances that are likely to revolutionize our views on synapse–glia interactions in the developing, adult and diseased brain

Neuron-Glial Interactions

Although lagging behind classical computational neuroscience, theoretical and computational approaches are beginning to emerge to characterize different aspects of neuron-glial interactions. This chapter aims to provide essential knowledge on neuron-glial interactions in the mammalian brain, leveraging on computational studies that focus on structure (anatomy) and function (physiology) of such interactions in the healthy brain. Although our understanding of the need of neuron-glial interactions in the brain is still at its infancy, being mostly based on predictions that await for experimental validation, simple general modeling arguments borrowed from control theory are introduced to support the importance of including such interactions in traditional neuron-based modeling paradigms.Comment: 43 pages, 2 figures, 1 table. Accepted for publication in the "Encyclopedia of Computational Neuroscience," D. Jaeger and R. Jung eds., Springer-Verlag New York, 2020 (2nd edition