Search

1.1. Background Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking infiltration of activated PBMCs into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS.1.2. Methods To establish our model, we first extracted PBMCs from rat spleen, then, immunologically primed PBMCs with lipopolysaccharide (LPS), followed by further activation with nigericin. Thereafter, we co-cultured these activated PBMCs with organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. We further targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 hours, we analyzed inflammation markers in the cortex and the hippocampus using semiquantitative immunofluorescence. In addition, we analyzed neuronal activity by whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons.1.3. Results In the cortex, co-culturing immunoreactive PBMCs treated with LPS + nigericin on top of OCHSCs upregulated inflammatory markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs (i.e. treated with LPS only), to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, protected them from neuroinflammation and hippocampal hyperexcitability.1.4. Conclusions Our study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity.

The article attempts to provide the theoretical fundamentals for the semiotic component of lacunae in a language. The definitions of the following notions have been represented: 1) lacunarity as a complex phenomenon that works in the modes of language, speech and speech behaviour; 2) lacuna as a gap, an empty space, which lacks something, which may be characteristic of a written work. The author of the article considers the main classes of lacunae, among which are: 1) generic lacunae, which reflect the absence of a common name for a class of objects; 2) species lacunae are the absence of specific names, names of individual types of objects or phenomena; 3) intralingual lacunae are found within the paradigms of one language; 4) interlanguage lacunae are revealed when comparing different languages: if one of them does not have the lexical equivalent of any unit of another language, then it is possible to speak about the existence of a lacuna in it; 5) grammatical lacunae are the result of phonetic, prosodic, morphological weakening or erosion of elements, which often become the cause of the approval of a new lexical, phonetic or grammatical form; 6) phonosemantic lacunae arise in line with the general linguistic tendency to phonetic harmoniousness, they are withdrawn from rare use.

Temporal lobe epilepsy is known to be associated with a past history of febrile seizures (FS). In this chapter, we will review models of FS using hyperthermia (HT) to mimic fever in order to provoke seizures. While fever results from pathological disruption of thermoregulation, hyperthermia is caused by the body absorbing more heat than it can dissipate, leading to the occurrence of hyperthermic seizures (HS). Since the first edition of this book, a great amount of studies have used HT models, modifying the methodology to improve them in an attempt to understand FS generation and its long-term epileptogenic effects. We will therefore focus on the findings in this field published since then. After a description of all HS models in the literature, we discuss in more details the widely used hair dryer model. Finally, we summarize the long-term repercussions of HS and their potential contribution to epileptogenesis in regards of such factors as age, sex, species, and strain.

Focal cortical dysplasia is a common cause of medication resistant epilepsy. A better understanding of its presentation, pathophysiology and consequences have helped us improved its treatment and outcome. This paper reviews the most recent classification, pathophysiology and imaging findings in clinical research as well as the knowledge gained from studying genetic and lesional animal models of focal cortical dysplasia. This review of this recently gained knowledge will most likely help develop new research models and new therapeutic targets for patients with epilepsy associated with focal cortical dysplasia.

The three-layered piriform cortex, an integral part of the olfactory system, processes odor information relayed by olfactory bulb mitral cells. Specifically, mitral cell axons form the lateral olfactory tract (LOT) by targeting lateral olfactory tract (lot) guidepost cells in the piriform cortex. While lot cells and other piriform cortical neurons share a pallial origin, the factors that specify their precise phenotypes are poorly understood. Here we show that in mouse, the proneural genesNeurog1andNeurog2are coexpressed in the ventral pallium, a progenitor pool that first gives rise to Cajal-Retzius (CR) cells, which populate layer I of all cortical domains, and later to layer II/III neurons of the piriform cortex. Using loss-of-function and gain-of-function approaches, we find thatNeurog1has a unique early role in reducing CR cell neurogenesis by temperingNeurog2's proneural activity. In addition,Neurog1andNeurog2have redundant functions in the ventral pallium, acting in two phases to first specify a CR cell fate and later to specify layer II/III piriform cortex neuronal identities. In the early phase,Neurog1andNeurog2are also required for lot cell differentiation, which we reveal are a subset of CR neurons, the loss of which prevents mitral cell axon innervation and LOT formation. Consequently, mutation ofTrp73, a CR-specific cortical gene, results in lot cell and LOT axon displacement.Neurog1andNeurog2thus have unique and redundant functions in the piriform cortex, controlling the timing of differentiation of early-born CR/lot cells and specifying the identities of later-born layer II/III neurons.

Background: The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture. Methodology/Principal Findings: In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam. Conclusions/Significance: We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and identify Pten as an integral component of a novel cell positioning pathway in the retina. © 2012 Cantrup et al.

Cajal-Retzius cells are essential pioneer neurons that guide neuronal migration in the developing neocortex. During development, Cajal-Retzius cells arise from distinct progenitor domains that line the margins of the dorsal telencephalon, or pallium. Here, we show that the proneural gene Ascl1 is expressed in Cajal-Retzius cell progenitors in the pallial septum, ventral pallium, and cortical hem. Using a short-term lineage trace, we demonstrate that it is primarily the Ascl1-expressing progenitors in the pallial septum and ventral pallium that differentiate into Cajal-Retzius cells. Accordingly, we found a small, albeit significant reduction in the number of Reelin(+) and Trp73(+) Cajal-Retzius cells in the Ascl1(-/-) neocortex. Conversely, using a gain-of-function approach, we found that Ascl1 induces the expression of both Reelin, a Cajal-Retzius marker, and Tbr1, a marker of pallial-derived neurons, in a subset of early-stage pallial progenitors, an activity that declines over developmental time. Taken together, our data indicate that the proneural gene Ascl1 is required and sufficient to promote the differentiation of a subset of Cajal-Retzius neurons during early neocortical development. Notably, this is the first study that reports a function for Ascl1 in the pallium, as this gene is best known for its role in specifying subpallial neuronal identities.

BackgroundProneural genes encode basic helix–loop–helix transcription factors that specify distinct neuronal identities in different regions of the nervous system. In the embryonic telencephalon, the proneural genesNeurog1andNeurog2specify a dorsal regional identity and glutamatergic projection neuron phenotype in the presumptive neocortex, but their roles in cell fate specification in the olfactory bulb, which is also partly derived from dorsal telencephalic progenitors, have yet to be assessed. Given that olfactory bulb development is guided by interactions with the olfactory epithelium in the periphery, where proneural genes are also expressed, we investigated the roles ofNeurog1andNeurog2in the coordinated development of these two olfactory structures.ResultsNeurog1/2are co-expressed in olfactory bulb progenitors, while onlyNeurog1is widely expressed in progenitors for olfactory sensory neurons in the olfactory epithelium. Strikingly, only a remnant of an olfactory bulb forms inNeurog1−/−;Neurog2−/−double mutants, while this structure is smaller but distinguishable inNeurog1−/−single mutants and morphologically normal inNeurog2−/−single mutants. At the cellular level, fewer glutamatergic mitral and juxtaglomerular cells differentiate inNeurog1−/−;Neurog2−/−double-mutant olfactory bulbs. Instead, ectopic olfactory bulb interneurons are derived from dorsal telencephalic lineages inNeurog1−/−;Neurog2−/−double mutants and to a lesser extent inNeurog2−/−single mutants. Conversely, cell fate specification is normal inNeurog1−/−olfactory bulbs, but aberrant patterns of cell proliferation and neuronal migration are observed inNeurog1−/−single andNeurog1−/−;Neurog2−/−double mutants, probably contributing to their altered morphologies. Finally, inNeurog1−/−andNeurog1−/−;Neurog2−/−embryos, olfactory sensory neurons in the epithelium, which normally project to the olfactory bulb to guide its morphogenesis, fail to innervate the olfactory bulb.ConclusionsWe have identified a cell autonomous role forNeurog1/2 in specifying the glutamatergic identity of olfactory bulb neurons. Furthermore,Neurog1(and notNeurog2) is required to guide olfactory sensory neuron innervation of the olfactory bulb, the loss of which results in defects in olfactory bulb proliferation and tissue morphogenesis. We thus conclude thatNeurog1/2together coordinate development of the olfactory system, which depends on tissue interactions between the olfactory bulb and epithelium.