Integrated Calendar

: Intracellular Ca2+ concentration ([Ca2+]i) is tightly regulated in neurons. Ca2+ plays important roles in signal transduction pathways, synaptic plasticity, energy metabolism and apoptosis. In dendritic spines, [Ca2+]i is controlled by voltage and ligand-gated channels that allow Ca2+ entry from the extracellular space and by ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R) that release Ca2+ from intracellular stores. Disruption in Ca2+ homeostasis is linked to several pathologies and is suggested to play a pivotal role in the cascade of events leading to Alzheimer disease (AD). In line with this, I found that low concentrations of caffeine, known to release Ca2+ from stores, is more effective in facilitating long-term potentiation (LTP) induction in hippocampal slices of a triple-transgenic (3xTg) mouse model of AD than controls. Synaptopodin (SP) is a protein residing in the dendritic spines. SP is an essential component in the formation of the spine apparatus (SA), which is a specialized form of smooth endoplasmic reticulum (ER) found in dendritic spines. Spines lacking SP were shown to release less Ca2+ from stores. The present study is aimed to explore the involvement of Ca2+ stores in 3xTg mouse model of AD. By crossing 3xTg and SPKO mice lines, I studied the effect of SP deficiency on AD markers in the 3xTg mouse. I found that the 3xTg/SPKO mice show normal learning in a spatial memory task by comparison to the deficiency found in the 3xTg mouse, and express normal LTP in hippocampal slices, which is deficient in 3xTg mice. Furthermore, low concentration of ryanodine has a facilitating effect on LTP induction only in the 3xTg mice group. In addition, these brains do not express amyloid plaques, activated microglia, p-tau overexpression and high RyR expression seen in age matched 3xTg mice, These results suggest that SP deficiency restores [Ca2+]i homeostasis in the 3xTg so as to suppress the progression of AD symptoms.

Membranes compartmentalize living matter into cells and subcellular structures. Many life processes involve membrane topological changes and remodelling: the uptake of materials via endocytosis and secretion by exocytosis, the generation of intra or extra-cellular vesicles as well as various membrane fusion processes. In order to get to the bottom of these fundamental physiological processes, it is vital to study membrane mechanical properties and membrane deformation. In this talk I will present the results of our research on several aspects of vesicle generation and membrane fusion using single molecule techniques. By means of an AFM force spectroscopy study we characterized the mechanical properties of small natural vesicles, called extracellular vesicles (EVs). Investigating the mechanical properties of these vesicles and their lipid and protein content provided new insights into the still poorly understood processes underlying vesicle generation. Acoustic Force Spectroscopy (AFS) was the choice for our novel methodology to measure cell mechanical properties. It enabled our finding that uptake of EVs by cells changes cellular deformability, a process that may have implications in several disease states where EV levels are significantly elevated, such as malaria and breast cancer. Combining optical tweezers with confocal fluorescence microscopy was the perfect tool for the investigation of membrane remodelling by calcium sensor proteins which are crucial in neuronal communication. We discovered surprising differences between the action mechanisms of two structurally similar proteins, Doc2b and Synaptotagmin-1 (Syt1), as determined by quantifying the strength and probabilities of protein-induced membrane-membrane interactions. Overall these fundamentally new insights into central biological processes were possible by our biophysical characterization of membranes using a powerful combination of single molecule techniques: Optical tweezers combined with confocal fluorescent microscopy, AFS and AFM.

Acquisition of motor skills often involves the concatenation of single movements into sequences. Along the course of learning, sequential performance becomes progressively faster and smoother, presumably by optimization of both motor planning and motor execution. Following its encoding during training, “how-to” memory undergoes consolidation, reflecting transformations in performance and its neurobiological underpinnings over time. This offline post-training memory process is characterized by two phenomena: reduced sensitivity to interference and the emergence of delayed, typically overnight, gains in performance. Successful learning is a result of strict control (gating) over the on-line and off-line stages of the experience-driven changes in the brain’s organization (neural plasticity). Factors, such as the amount of practice, the passage of time and the affordance of sleep and factors specific to the learning environment may selectively affect, – block or accelerate, - the expression of delayed gains in motor performance. These factors interact in a complex, non-linear manner. Developmental and inter-individual differences impose additional constraints on memory processes (e.g., age, chronotype, clinical condition).
High-level reorganization of the movements as a unit following practice was shown to be subserved by optimization of planning and execution of individual movements. Temporal and kinematic analysis of performance demonstrated that only the offline inter-movement interval shortening (co-articulation) is selectively blocked by the interference experience, while velocity and amplitude, comprising movement time, are interference–insensitive. Sleep, including a day-time sleep, reduces the susceptibility of the memory trace to retroactive behavioural interference and also accelerates the expression of delayed gains in performance. Activity in cortico-striatal areas that was disrupted during the day due to interference and accentuated in the absence of a day-time sleep is restored overnight. Additional line of experiments showed that on-line environmental noise during training (vibro-auditory task-irrelevant stimulation) may be an important modulator of memory consolidation; its impact is ambiguous, presumably contingent on baseline arousal levels of the individual.

1. Albouy G., King B. R., Schmidt C., Desseilles M., Dang-Vu T., Balteau E., Phillips C., Degueldre C., Orban P., Benali H., Peigneux P., Luxen A., Karni A., Doyon J., Maquet P., Korman M. 2016 Cerebral Activity Associated with Transient Sleep-Facilitated Reduction in Motor Memory Vulnerability to Interference Scientific Reports 6:34948
2. Friedman J., Korman M. 2016 Offline optimization of the relative timing of movements in a sequence is blocked by behavioral retroactive interference Frontiers in Human Neuroscience, 10:623
3. Korman M., Herling Z., Levy I., Egbarieh N., Engel-Yeger B., Karni A. 2017 Background matters: minor vibratory sensory stimulation during motor skill acquisition selectively reduces off-line memory consolidation. Neurobiology of Learning and Memory 140:27-32

A-T-Al aluminides (where A = actinide/lanthanide/rare earth elements and T=transition metal) were intensively studied due to their ability to form heavy fermion compounds that could possess unique physical properties [1-3, for example]. Although A-T-Al family contains hundreds of phases, they can be classified into only a few series of phases with isotypical structures. Al richest are: tetragonal ATxAl12-x (ThMn12 type), tetragonal AT2Al10 (CaCr2Al10 type), orthorhombic AT2Al10 (YbFe2Al10 type) and cubic AT2Al20 (CeCr2Al20 type). Due to the intimate link between structure and properties, in order to understand and enhance physical properties – exact atomic structure of these materials should be known. Such researches are performed usually using “trial and error” approach, e.g. cast and characterize, which could be time consuming. It would be of clear benefit to formulate a rule that could predict the relative stability of the structures that may form in the ternary Al-richest phases in the A-T-Al systems.
Current research was conducted with an aim to understand the influence of A and T atom types on the formation of the stable structures in the AT2Al20 alloys. The work was performed systematically, investigating several AT2Al20 alloys both experimentally and by Density Functional theory (DFT) calculations. Study on the ThT2Al20 systems (where T=Ti, V, Cr, Mn and Fe) was previously performed by our group suggesting that the magnetic moment of T atoms can be used as a good descriptor of phase stability [4-5]. Now, we focus on the investigation of the AMn2Al20, where A elements were selected according to their electronic structure. Theoretical and experimental results were found to be in perfect agreement. By analyzing the density of states (DOS) we found that the different behavior of the 4f and 5f-shell electrons of the heavy atom, eventually determines which structure will be favorable [6].
While studying these A-T-Al systems new unknown ternary phases were discovered: Th2Ni10Al15 [7] and Nd2Re3Al15. Since in both cases the alloys of an interest did not attain equilibrium state despite the prolonged heat treatments - they contained multiple phases. Therefore, electron crystallography methods were the only viable tool applicable for structure solution of these phases. In current research, electron diffraction tomography (EDT) approach was successfully used for solution of atomic structure of both phases.