Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling–induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.

Recent case reports provided alarming signals that treatment with bortezomib might be associated with cardiac events. In all reported cases, patients experiencing cardiac problems were previously or concomitantly treated with other chemotherapeutics including cardiotoxic anthracyclines. Therefore, it is difficult to distinguish which components of the therapeutic regimens contribute to cardiotoxicity. Here, we addressed the influence of bortezomib on cardiac function in rats that were not treated with other drugs. Rats were treated with bortezomib at a dose of 0.2 mg/kg thrice weekly. Echocardiography, histopathology, and electron microscopy were used to evaluate cardiac function and structural changes. Respiration of the rat heart mitochondria was measured polarographically. Cell culture experiments were used to determine the influence of bortezomib on cardiomyocyte survival, contractility,

Studies in cultured cells have demonstrated the existence of higher-order epigenetic mechanisms, determining the relationship between expression of the gene and its position within the cell nucleus. It is unknown, whether such mechanisms operate in postmitotic, highly differentiated cell types, such as neurons in vivo. Accordingly, we examined whether the intranuclear positions of Bdnf and Trkb genes, encoding the major neurotrophin and its receptor respectively, change as a result of neuronal activity, and what functional consequences such movements may have. In a rat model of massive neuronal activation upon kainate-induced seizures we found that elevated neuronal expression of Bdnf is associated with its detachment from the nuclear lamina, and translocation toward the nucleus center. In contrast, the position of stably expressed Trkb remains unchanged after seizures. Our study demonstrates that activation-dependent architectural remodeling of the neuronal cell nucleus in vivo contributes to activity-dependent changes in gene expression in the brain.

Granular Co 10 Cu 90 alloys displaying giant magnetoresistance have been obtained by melt spinning followed by an appropriate heat treatment in the range 0-700°C. Their structural and magnetic properties have been studied on a microscopic scale using 59 Co NMR technique and thermoremanent magnetization measurements. The study reveals that in the as-quenched samples Co is involved in two main structural components: small, irregular, strained Co particles ͑60% of the entire Co population͒ and a composition modulated CoCu alloy. A high modulation amplitude of the concentration profile in the alloy subdivides the latter in two parts with distinctly different properties. One part consists of ferromagnetic alloy ͑average Cu concentration of about 20%͒ with a blocking temperature of about 35 K ͑involving 6% of the entire Co population in a sample͒. The other part, containing the remaining 34% of the entire Co population, is a paramagnetic alloy with a blocking temperature below 4.2 K. The ferromagnetic alloy is magnetically soft-its transverse susceptibility is lower by a factor of 7 than the transverse susceptibility of the quenched-in Co particles. The latter population has a blocking temperature of about 150-200 K. During the heat treatment, each of the two main structural components undergoes respective decomposition processes: both of them display two temperature regimes. One process consists in dissolving the quenched-in Co particles after annealing at around 400°C, followed at higher temperatures by a nucleation and growth of the more regular in shape Co particles. The other process resembles a spinodal decomposition of the quenched-in CoCu alloy, resulting in sharpening of the concentration profile and eventually leading to Co cluster formation in samples annealed above 450°C. Both processes end at about T an ϭ700°C, in formation of large, pure Co clusters that are ferromagnetic at least up to 400 K.