Astrocytes in Neural Circuits: Key Factors in Synaptic Regulation and Potential Targets for Neurodevelopmental Disorders

Astrocytes are the major glial cells in the brain, which play a supporting role in the energy and nutritional supply of neurons. They were initially regarded as passive space-filling cells, but the latest progress in the study of the development and function of astrocytes highlights their active roles in regulating synaptic transmission, formation, and plasticity. In the concept of “tripartite synapse,” the bidirectional influence between astrocytes and neurons, in addition to their steady-state and supporting function, suggests that any negative changes in the structure or function of astrocytes will affect the activity of neurons, leading to neurodevelopmental disorders. The role of astrocytes in the pathophysiology of various neurological and psychiatric disorders caused by synaptic defects is increasingly appreciated. Understanding the roles of astrocytes in regulating synaptic development and the plasticity of neural circuits could help provide new treatments for these diseases.

HGG-21. MALIGNANT SYNAPTIC PLASTICITY IN PEDIATRIC HIGH-GRADE GLIOMAS

Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicate the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.

Calsyntenin-3, an atypical cadherin, suppresses inhibitory basket- and stellate-cell synapses but boosts excitatory parallel-fiber synapses in cerebellum

Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic adaptors for kinesin-mediated vesicular transport. Here, we show that acute CRISPR-mediated deletion of calsyntenin-3 in cerebellar Purkinje cells in vivo causes a large decrease in inhibitory synapses, but a surprisingly robust increase in excitatory parallel-fiber synapses. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Thus, by promoting formation of an excitatory type of synapses and decreasing formation of an inhibitory type of synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells. No similarly opposing function of a synaptic adhesion molecule was previously observed, suggesting a new paradigm of synaptic regulation.

Biomedical Implications of Plant-Based Principles as Antidepressants: Prospects for Novel Drug Development

Background: Depression is a most common mental disorder. The symptoms of depression include loss of energy, changes in appetite, more or less sleep, anxiety, low concentration, uncertainty, restlessness, feelings of worthlessness, guilt, or despair, and thoughts of self-harm or suicide. In order to provide safe, efficient and cost-effective medication, the plants based principles in isolation or in combination with traditional antidepressants are attracting increasing attention for depression therapy. Method: The information regarding the present review and its contents such as collected from published literature materials in different international journals. We have used different search engines such as PubMed, Medline, ResearchGate Google Semantic Scholar and ScienceDirect. For this purpose, the data obtained were properly organized and suitably analyzed to include in this article. Results: Most of the phytomolecules isolated from the medicinal plants display antidepressant effect through the synaptic regulation of levels of neurotransmitters such as dopamine, serotonin, and noradrenaline in different parts of the brain. The mechanism of action of phytomolecules also involves negative regulation of the activities of monoamine oxidase (MAO) and acetylcholinesterase (AChE) and prevention of hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis. In addition, the strong antioxidative and antiinflamatory potential of these phytochemicals offer synergy to their antidepressant as well as antipsychosomatic functions. Conclusion: The application of phytochemicals has proved it to be a safe, cost effective and efficient therapeutic agent to treat the patients suffering from mild to severe state of depression and other psychiatric disorders. The potential phytochemicals may be further optimized using in silico tools to develop better antidepressants and antisychotic agents in future.

Dynamic bi-directional phosphorylation events associated with the reciprocal regulation of synapses during homeostatic up- and down-scaling

SummaryHomeostatic synaptic scaling allows for bi-directional adjustment of the strength of synaptic connections in response to changes in their input. Protein phosphorylation modulates many neuronal and synaptic processes, but it has not been studied on a global, proteome-wide scale during synaptic scaling. To examine this, we used LC-MS/MS analyses to measure changes in the phosphoproteome in response to up- or down-scaling in cultured cortical neurons over minutes to 24 hours. Out of 45,000 phosphorylation events measured, ~3,300 (associated with 1,280 phospho-proteins) were regulated by homeostatic scaling. The activity-sensitive phosphoproteins were predominantly located at synapses and involved in cytoskeletal reorganization. We identified many early transient phosphorylation events which could serve as sensors for the activity offset as well as late and/or persistent phosphoregulation that could represent effector mechanisms driving the homeostatic response. Much of the persistent phosphorylation was reciprocally regulated by up- or down-scaling, suggesting that the mechanisms underlying these two poles of synaptic regulation make use of a common signaling axis.

Molecular Mechanisms of L1 and NCAM Adhesion Molecules in Synaptic Pruning, Plasticity, and Stabilization

Mammalian brain circuits are wired by dynamic formation and remodeling during development to produce a balance of excitatory and inhibitory synapses. Synaptic regulation is mediated by a complex network of proteins including immunoglobulin (Ig)- class cell adhesion molecules (CAMs), structural and signal-transducing components at the pre- and post-synaptic membranes, and the extracellular protein matrix. This review explores the current understanding of developmental synapse regulation mediated by L1 and NCAM family CAMs. Excitatory and inhibitory synapses undergo formation and remodeling through neuronal CAMs and receptor-ligand interactions. These responses result in pruning inactive dendritic spines and perisomatic contacts, or synaptic strengthening during critical periods of plasticity. Ankyrins engage neural adhesion molecules of the L1 family (L1-CAMs) to promote synaptic stability. Chondroitin sulfates, hyaluronic acid, tenascin-R, and linker proteins comprising the perineuronal net interact with L1-CAMs and NCAM, stabilizing synaptic contacts and limiting plasticity as critical periods close. Understanding neuronal adhesion signaling and synaptic targeting provides insight into normal development as well as synaptic connectivity disorders including autism, schizophrenia, and intellectual disability.