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Fonseca R.,Gulbenkian Institute of Science

Fear conditioning, a form of associative learning is thought to involve the induction of an associative long-term potentiation of cortical and thalamic inputs to the lateral amygdala. Here, we show that stimulation of the thalamic input can reinforce a transient form of plasticity (E-LTP) induced by weak stimulation of the cortical inputs. This synaptic cooperation occurs within a time window of 30 min, suggesting that synaptic integration at amygdala synapses can occur within large time windows. Interestingly, we found that synaptic cooperation is not symmetrical. Reinforcement of a thalamic E-LTP by subsequent cortical stimulation is only observed within a shorter time window. We found that activation of endocannabinoid CB1 receptors is involved in the time restriction of thalamic and cortical synaptic cooperation in an activity-dependent manner. Our results support the hypothesis that synaptic cooperation can underlie associative learning and that synaptic tagging and capture is a general mechanism in synaptic plasticity. © 2013 American College of Neuropsychopharmacology. All rights reserved. Source

Deehan M.,NovImmune | Garces S.,Gulbenkian Institute of Science | Garces S.,Research Center | Kramer D.,Sanofi S.A. | And 4 more authors.
Autoimmunity Reviews

All protein drugs (biologicals) have an immunogenic potential and we are armed with multiple guidelines, regulatory documents and white papers to assist us in assessing the level of risk for unwanted immunogenicity of new biologicals. However, for certain biologicals, significant immunogenicity becomes only apparent after their use in patients. Causes of immunogenicity are multifactorial but not yet fully understood. Within the pharmaceutical industry there are only a few opportunities to openly discuss the causes and consequences of immunogenicity with regard to the development of new biologicals. The annual Open Scientific Symposium of the European Immunogenicity Platform (EIP) is one such meeting that brings together scientists and clinicians from academia and industry to build know-how and expertise in the field of immunogenicity. The critical topics discussed at the last EIP meeting (February 2014) will be reviewed here. The current opinion of this expert group is that the assessment of unwanted immunogenicity can be improved by using prediction tools, optimizing the performance of immunogenicity assays and learning from the clinical impact of other biologicals that have already been administered to patients. A multidisciplinary approach is warranted to better understand and minimize drug immunogenicity and its clinical consequences. However, this prediction does not directly translate to the immunogenicity observed in clinical practice. In parallel, such immune-monitoring will provide important information to help us understand the human immune response to biologic therapies. © 2015 Elsevier B.V. Source

Fonseca R.,Gulbenkian Institute of Science
Synaptic Tagging and Capture: From Synapses to Behavior

Activity-dependent plasticity of synaptic connections is a hallmark of the mammalian brain and represents a key mechanism for rewiring neural circuits during development, experience-dependent plasticity, and brain disorders. Understanding the rules that determine how different neuronal inputs interact with each other, allow us to gain insight on the cellular and molecular mechanisms involved in memory establishment and maintenance. One of the most intriguing aspects of memory formation is the observation that past and ongoing activity can infl uence how information is processed and maintained in the brain. At the cellular level, the synaptic tagging and capture (STC) theory states that the maintenance of activity-dependent synaptic changes is based on the interaction between synaptic-specific tags and the capture of plasticity-related proteins. The STC has provided a solid framework to account for the input specifi city of synaptic plasticity but also provides a working model to understand the heterosynaptic interaction between different groups of synapses. In this chapter, I will discuss the evidence regarding the cooperative and competitive interactions between different groups of synapses. In particular, I will address the properties of synaptic cooperation and competition that contribute to the refi nement of neuronal connections during development. Later, I will address the evidence that similar rules operate during the induction and maintenance of synaptic plasticity. Due to the intricate relationship between synaptic plasticity and memory formation, understanding the cellular rules of cooperative and competitive interactions between synapses, will allow us to further dissect the rules underlying associative learning. © Springer Science+Business Media New York 2015. Source

Ten Broek C.M.A.,University of Antwerp | Ten Broek C.M.A.,Naturalis Biodiversity Center | Bots J.,University of Antwerp | Varela-Lasheras I.,Gulbenkian Institute of Science | And 3 more authors.

Fluctuating asymmetry (FA), as an indirect measure of developmental instability (DI), has been intensively studied for associations with stress and fitness. Patterns, however, appear heterogeneous and the underlying causes remain largely unknown. One aspect that has received relatively little attention in the literature is the consequence of direct mechanical effects on asymmetries. The crucial prerequisite for FA to reflect DI is that environmental conditions on both sides should be identical. This condition may be violated during early human development if amniotic fluid volume is deficient, as the resulting mechanical pressures may increase asymmetries. Indeed, we showed that limb bones of deceased human fetuses exhibited increased asymmetry, when there was not sufficient amniotic fluid (and, thus, space) in the uterine cavity. As amniotic fluid deficiency is known to cause substantial asymmetries and abnormal limb development, these subtle asymmetries are probably at least in part caused by the mechanical pressures. On the other hand, deficiencies in amniotic fluid volume are known to be associated with other congenital abnormalities that may disturb DI. More specifically, urogenital abnormalities can directly affect/reduce amniotic fluid volume. We disentangled the direct mechanical effects on FA from the indirect effects of urogenital abnormalities, the latter presumably representing DI. We discovered that both factors contributed significantly to the increase in FA. However, the direct mechanical effect of uterine pressure, albeit statistically significant, appeared less important than the effects of urogenital abnormalities, with an effect size only two-third as large. We, thus, conclude that correcting for the relevant direct factors allowed for a representative test of the association between DI and stress, and confirmed that fetuses form a suitable model system to increase our understanding in patterns of FA and symmetry development. © 2013 ten Broek et al. Source

Gutermuth T.,Gulbenkian Institute of Science | Gutermuth T.,University of Wurzburg | Lassig R.,Free University of Berlin | Portes M.-T.,Gulbenkian Institute of Science | And 9 more authors.
Plant Cell

Apical growth in pollen tubes (PTs) is associated with the presence of tip-focused ion gradients and fluxes, implying polar localization or regulation of the underlying transporters. The molecular identity and regulation of anion transporters in PTs is unknown. Here we report a negative gradient of cytosolic anion concentration focused on the tip, in negative correlation with the cytosolic Ca2+ concentration. We hypothesized that a possible link between these two ions is based on the presence of Ca2+-dependent protein kinases (CPKs). We characterized anion channels and CPK transcripts in PTs and analyzed their localization. Yellow fluorescent protein (YFP) tagging of a homolog of SLOW ANION CHANNEL-ASSOCIATED1 (SLAH3:YFP) was widespread along PTs, but, in accordance with the anion efflux, CPK2/CPK20/CPK17/CPK34:YFP fluorescence was strictly localized at the tip plasma membrane. Expression of SLAH3 with either CPK2 or CPK20 (but not CPK17/CPK34) in Xenopus laevis oocytes elicited S-type anion channel currents. Interaction of SLAH3 with CPK2/CPK20 (but not CPK17/CPK34) was confirmed by Förster-resonance energy transfer fluorescence lifetime microscopy in Arabidopsis thaliana mesophyll protoplasts and bimolecular fluorescence complementation in living PTs. Compared with wild-type PTs, slah3-1 and slah3-2 as well as cpk2-1 cpk20-2 PTs had reduced anion currents. Doublemutant cpk2-1 cpk20-2 and slah3-1 PTs had reduced extracellular anion fluxes at the tip. Our studies provide evidence for a Ca2+-dependent CPK2/CPK20 regulation of the anion channel SLAH3 to regulate PT growth. © 2013 American Society of Plant Biologists. All rights reserved. Source

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