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Spinal cord injury (SCI) causes temporary disabilities or permanent effects including neuropathic pain and spastiscity. The damage often results from mechanical trauma, which in turn triggers the neuroinflammatory process. Neuroinflammation plays essential roles in the structural, biochemical, and cellular changes that take place in the spinal cord after the injury. Indeed, SCI activates many different signaling pathways that coordinate the resulting cellular responses. While neuroinflammation serves as a physiological reaction to harmful stimuli, it is clear that long-lasting inflammatory response leads to aggravation of the neurodegenerative processes, becoming detrimental to recovery post-injury. In this context, we present some possible therapeutic targets in these activated signaling pathways and provide new perspectives for SCI treatment based on recently developed technologies, including clustered regularly interspaced short palindromic repeats (CRISPR)-based methods (including prime editing), optogenetics, and designer receptor exclusively activated by designer drugs (DREADDs). We critically analyze the recent advances in the deployment of these methods focusing on the control of the initial neuroinflammatory response. We then propose alternatives and provide new avenues for SCI treatment based on these emerging technologies.

Histone post-translational modification has been shown to play a pivotal role in regulating gene expression and fate determination during the development of the central nervous system. Application of pharmacological blockers that control histone methylation status has been considered a promising avenue to control abnormal developmental processes and diseases as well. In this study, we focused on the role of potent histone demethylase inhibitor GSK-J1 as a blocker of Jumonji domain-containing protein 3 (Jmjd3) in early postnatal retinal development. Jmjd3 participates in different processes such as cell proliferation, apoptosis, differentiation, senescence, and cell reprogramming via demethylation of histone 3 lysine 27 trimethylation status (H3K27 me3). As a first approach, we determined the localization of Jmjd3 in neonate and adult rat retina. We observed that Jmjd3 accumulation is higher in the adult retina, which is consistent with the localization in the differentiated neurons, including ganglion cells in the retina of neonate rats. At this developmental age, we also observed the presence of Jmjd3 in undifferentiated cells. Also, we confirmed that GSK-J1 caused the increase in the H3k27 me3 levels in the retinas of neonate rats. We next examined the functional consequences of GSK-J1 treatment on retinal development. Interestingly, injection of GSK-J1 simultaneously increased the number of proliferative and apoptotic cells. Furthermore, an increased number of immature cells were detected in the outer plexiform layer, with longer neuronal processes. Finally, the influence of GSK-J1 on postnatal retinal cytogenesis was examined. Interestingly, GSK-J1 specifically caused a significant decrease in the number of PKCα-positive cells, which is a reliable marker of rod-on bipolar cells, showing no significant effects on the differentiation of other retinal subtypes. To our knowledge, these data provide the first evidence that in vivo pharmacological blocking of histone demethylase by GSK-J1 affects differentiation of specific neuronal subtypes. In summary, our results indisputably revealed that the application of GSK-J1 could influence cell proliferation, maturation, apoptosis induction, and specific cell determination. With this, we were able to provide evidence that this small molecule can be explored in therapeutic strategies for the abnormal development and diseases of the central nervous system.

Epilepsy is a disorder of the brain characterized by the predisposition to generate recurrent unprovoked seizures, which involves reshaping of neuronal circuitries based on intense neuronal activity. In this review, we first detailed the regulation of plasticity-associated genes, such as ARC, GAP-43, PSD-95, synapsin, and synaptophysin. Indeed, reshaping of neuronal connectivity after the primary, acute epileptogenesis event increases the excitability of the temporal lobe. Herein, we also discussed the heterogeneity of neuronal populations regarding the number of synaptic connections, which in the theoretical field is commonly referred as degree. Employing integrate-and-fire neuronal model, we determined that in addition to increased synaptic strength, degree correlations might play essential and unsuspected roles in the control of network activity. Indeed, assortativity, which can be described as a condition where high-degree correlations are observed, increases the excitability of neural networks. In this review, we summarized recent topics in the field, and data were discussed according to newly developed or unusual tools, as provided by mathematical graph analysis and high-order statistics. With this, we were able to present new foundations for the pathological activity observed in temporal lobe epilepsy.

The Zika virus (ZIKV) outbreak that occurred in the northeast of Brazil in 2015 led to alarming numbers of babies born with microcephaly in this region. Since then, several studies have evaluated the relationship between ZIKV infection and development of the malformation although the specific mechanistic interaction between ZIKV and human physiological processes that ultimately manifest as microcephaly remains debated. Importantly, most current studies did not consider the specificities of the biology and life cycle of ZIKV. As a consequence, specificities of the infection on the developing central nervous system (CNS) were frequently disregarded. In order to begin to address this important gap in our knowledge, we have collated and critically reviewed the existing evidence in this area to identify any emerging consensus on this topic and thereafter describe possible mechanisms by which ZIKV infection could interfere with specific processes of CNS development, such as neuronal proliferation, and the complex interactions of immature neurons with radial glial cells. With this, we were able to present the current knowledge on this important topic in the neurobiology field.

It is well known that calcium (Ca 2+ ) is involved in the triggering of neuronal death. Ca 2+ cytosolic levels are regulated by Ca 2+ release from internal stores located in organelles, such as the endoplasmic reticulum. Indeed, Ca 2+ transit from distinct cell compartments follows complex dynamics that are mediated by specific receptors, notably inositol trisphosphate receptors (IP3Rs). Ca 2+ release by IP3Rs plays essential roles in several neurological disorders; however, details of these processes are poorly understood. Moreover, recent studies have shown that subcellular location, molecular identity, and density of IP3Rs profoundly affect Ca 2+ transit in neurons. Therefore, regulation of IP3R gene products in specific cellular vicinities seems to be crucial in a wide range of cellular processes from neuroprotection to neurodegeneration. In this regard, microRNAs seem to govern not only IP3Rs translation levels but also subcellular accumulation. Combining new data from molecular cell biology with mathematical modelling, we were able to summarize the state of the art on this topic. In addition to presenting how Ca 2+ dynamics mediated by IP3R activation follow a stochastic regimen, we integrated a theoretical approach in an easy-to-apply, cell biology-coherent fashion. Following the presented premises and in contrast to previously tested hypotheses, Ca 2+ released by IP3Rs may play different roles in specific neurological diseases, including Alzheimer's disease and Parkinson's disease.

Extracellular vesicles (EVs), including exosomes, microvesicles and apoptotic bodies, participate in intercellular communication, and particularly, in paracrine and endocrine signalling. The EVs and their specific contents have been considered hallmarks of different diseases. It has been recently discovered that EVs can co-transport nucleic acids such as DNAs, ribosomal RNAs, circular RNAs (circRNAs), long noncoding RNAs (lnRNAs) and microRNAs (miRNAs). miRNAs are important regulators of gene expression at the post-transcriptional level, although they may also play other roles. Recent evidence supports the hypothesis that miRNAs can activate Toll-like receptors (TLRs) under certain circumstances. TLRs belong to a multigene family of immune system receptors and have been recently described in the nervous system. In the immune system, TLRs are important for the recognition of the invading microorganisms, whereas in the nervous system, they recognise endogenous ligands released by undifferentiated or necrotic/injured cells. In the neuronal disease field, TLRs activity has been associated with amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's and Parkinson's disease. Herein, we reviewed the current knowledge of the relationship between miRNA release by EVs and the inflammation signalling triggered by TLRs in neighbouring cells or during long-distance cell-to-cell communication. We highlight novel aspects of this communication mechanism, offering a valuable insight into such pathways in health and disease.

MicroRNAs (miRNAs) are short nucleotides sequences that regulate the expression of genes in different eukaryotic cell types. A tremendous amount of knowledge on miRNAs has rapidly accumulated over the last few years, revealing the growing interest in this field of research. On the other hand, clarifying the physiological regulation of gene expression in the central nervous system is important for establishing a reference for comparison to the diseased state. It is well known that the fine tuning of neuronal networks relies on intricate molecular mechanisms, such as the adjustment of the synaptic transmission. As determined by recent studies, regulation of neuronal interactions by miRNAs has critical consequences in the development, adaptation to ambient demands, and degeneration of the nervous system. In contrast, activation of synaptic receptors triggers downstream signaling cascades that generate a vast array of effects, which includes the regulation of novel genes involved in the control of the miRNA life cycle. In this review, we have examined the hot topics on miRNA gene-regulatory activities in the broad field of neuronal communication-related processes. Furthermore, in addition to indicating the newly described effect of miRNAs on the regulation of specific neurotransmitter systems, we have pointed out how these systems affect the expression, transport, and stability of miRNAs. Moreover, we discuss newly described and under-investigation mechanisms involving the intercellular transfer of miRNAs, aided by exosomes and gap junctions. Thus, in the current review, we were able to highlight recent findings related to miRNAs that indisputably contributed towards the understanding of the nervous system in health and disease.