RESUMEN

The Flaviviridae family comprises positive-sense single-strand RNA viruses mainly transmitted by arthropods. Many of these pathogens are especially deleterious to the nervous system, and a myriad of neurological symptoms have been associated with infections by Zika virus (ZIKV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) in humans. Studies suggest that viral replication in neural cells and the massive release of pro-inflammatory mediators lead to morphological alterations of synaptic spine structure and changes in the balance of excitatory/inhibitory neurotransmitters and receptors. Glutamate is the predominant excitatory neurotransmitter in the brain, and studies propose that either enhanced release or impaired uptake of this amino acid contributes to brain damage in several conditions. Here, we review existing evidence suggesting that glutamatergic dysfunction-induced by flaviviruses is a central mechanism for neurological damage and clinical outcomes of infection. We also discuss current data suggesting that pharmacological approaches that counteract glutamatergic dysfunction show benefits in animal models of such viral diseases.

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RESUMEN

Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-ß family, TGF-beta 1 (TGF-ß1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-ß1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-ß1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-ß1 and its receptor, TßRII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1-P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-ß receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-ß1. Treatment of granular cell cultures with TGF-ß1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on TßRI activation because addition of a pharmacological inhibitor of TGF-ß, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-ß1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons.

RESUMEN

Brain function depends critically on the coordinated activity of presynaptic and postsynaptic signals derived from both neurons and non-neuronal elements such as glial cells. A key role for astrocytes in neuronal differentiation and circuitry formation has emerged within the last decade. Although the function of glial cells in synapse formation, elimination and efficacy has greatly increased, we are still very far from deeply understanding the molecular and cellular mechanism underlying these events. The present review discusses the mechanisms driving astrocytic control of excitatory and inhibitory synapse formation in the central nervous system, especially the mechanisms mediated by soluble molecules, particularly those from the TGF-ß family. Further, we discuss whether and how human astrocytes might contribute to the acquisition of human cognition. We argue that understanding how astrocytic signals regulate synaptic development might offer new insights into human perception, learning, memory, and cognition and, ultimately, provide new targets for the treatment of neurological diseases.

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