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Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation–inhibition balance in the brain, and it can serve as a mouse model of epilepsy. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.06.040 Byline: Olga Britanova (a)(f), Pavlos Alifragis (a)(b), Stephan Junek (a), Kevin Jones (d), Peter Gruss (c), Victor Tarabykin (a)(e) Keywords: Cerebral cortex; Reelin; Transcription factor; Migration; Cre; Transgenic; Cell fate; Subiculum Abstract: Projection neurons of the developing cerebral cortex are generated in the cerebral ventricular zone and subsequently move to the developing cortical plate via radial migration. Conversely, most inhibitory interneurons originate in the ganglionic eminences and enter the developing cortical plate by tangential migration. Using immunohistochemical analysis together with tracer labeling experiments in organotypic brain slices, we show that a portion of cortical projection neurons migrates tangentially over long distances. Lineage analysis revealed that these neurons are derived from Emx1+ cortical progenitors and express the transcription factor Satb2 but do not express GABA or Olig1. In vitro and in vivo analysis of reeler mutant brains demonstrated that although reeler mutation does not influence tangential migration of interneurons, it affects the tangential migration of cortical projection neurons. Author Affiliation: (a) Department of Molecular Biology of Neuronal Signals, Max-Plank-Institute for Experimental Medicine, 37075 Gottingen, Germany (b) School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, UK (c) Department of Molecular Cell Biology, Max-Planck-Institute for Biophysical Chemistry, 37077 Gottingen, Germany (d) Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA (e) DFG Research Center for the Molecular Physiology of the Brain (CMPB), Germany (f) Laboratory of Molecular Technologies, Shemiakin and Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya 16/10, 117871 Moscow, Russia Article History: Received 6 October 2005; Revised 21 June 2006; Accepted 23 June 2006

The in vivo functions of murine gene Satb2 are studied, and it is found that similar to the way in which the gene SATB2 is perceived to act in humans, craniofacial defects due to haploinsuficiency of Satb2 including cleft palate, phenocopy those seen with 2q32-33 deletions and translocations in humans. Since jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification play crucial roles in jaw and palate development and etiology of craniofacial malformations.

As in many other animals, the primordial germ cells (PGCs) in avian and reptile embryos are specified in positions distinct from the positions where they differentiate into sperm and egg. Unlike in other organism however, in these embryos, the PGCs use the vascular system as a vehicle to transport them to the region of the gonad where they exit the blood vessels and reach their target. To determine the molecular mechanisms governing PGC migration in these species, we have investigated the role of the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) in guiding the cells towards their target in the chick embryo. We show that sdf-1 mRNA is expressed in locations where PGCs are found and towards which they migrate at the time they leave the blood vessels. Ectopically expressed chicken SDF-1[alpha] led to accumulation of PGCs at those positions. This analysis, as well as analysis of gene expression and PGC behavior in the mouse embryo, suggest that in both organisms, SDF-1 functions during the second phase of PGC migration, and not at earlier phases. These findings suggest that SDF-1 is required for the PGCs to execute the final migration steps as they transmigrate through the blood vessel endothelium of the chick or the gut epithelium of the mouse. Keywords: PGC; Chicken; Cell migration; Chemotaxis; Guidance; Chemokine; SDF-1; CXCL12; CXCR4; Dead end

This study aimed to investigate the connection between the mutation of the Sip1 transcription factor and impaired Ca2+-signaling, which reflects changes in neurotransmission in the cerebral cortex in vitro. We used mixed neuroglial cortical cell cultures derived from Sip1 mutant mice. The cells were loaded with a fluorescent ratiometric calcium-sensitive probe Fura-2 AM and epileptiform activity was modeled by excluding magnesium ions from the external media or adding a GABA(A) receptor antagonist, bicuculline. Intracellular calcium dynamics were recorded using fluorescence microscopy. To identify the level of gene expression, the Real-Time PCR method was used. It was found that cortical neurons isolated from homozygous (Sip1fl/fl) mice with the Sip1 mutation demonstrate suppressed Ca2+ signals in models of epileptiform activity in vitro. Wild-type cortical neurons are characterized by synchronous high-frequency and high-amplitude Ca2+ oscillations occurring in all neurons of the network in response to Mg2+-free medium and bicuculline. But cortical Sip1fl/fl neurons only single Ca2+ pulses or attenuated Ca2+ oscillations are recorded and only in single neurons, while most of the cell network does not respond to these stimuli. This signal deficiency of Sip1fl/fl neurons correlates with a suppressed expression level of the genes encoding the subunits of NMDA, AMPA, and KA receptors; protein kinases PKA, JNK, CaMKII; and also the transcription factor Hif1α. These negative effects were partially abolished when Sip1fl/fl neurons are grown in media with anti-inflammatory cytokine IL-10. IL-10 increases the expression of the above-mentioned genes but not to the level of expression in wild-type. At the same time, the amplitudes of Ca2+ signals increase in response to the selective agonists of NMDA, AMPA and KA receptors, and the proportion of neurons responding with Ca2+ oscillations to a Mg2+-free medium and bicuculline increases. IL-10 restores neurotransmission in neuronal networks with the Sip1 mutation by regulating the expression of genes encoding signaling proteins. [ABSTRACT FROM AUTHOR]