Publications

Background Cellular prion protein (PrP(C)) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrP(C) in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrP(C) is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrP(C), with some functions recently shown to be misattributed to PrP(C) due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrP(C) in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp(0/0) mouse model (Prnp(ZH3/ZH3)). Results We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in Prnp(ZH3/ZH3) animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of Prnp(ZH3/ZH3) vs wildtype mice. PrP(C) absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the Prnp(ZH3/ZH3) hippocampus. In addition, we observed a delay in neuronal maturation and network formation in Prnp(ZH3/ZH3) cultures. Conclusion Our results demonstrate that PrP(C) promotes neuronal network formation and connectivity. PrP(C) mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

JTD Keywords: anxiety, behavior, cellular prion protein, epilepsy, hippocampus, Anxiety, Behavior, Cellular prion protein, Developmental expression, Epilepsy, Gene-expression, Hippocampus, Kainate-induced seizures, Lacking, Ltp, Memory, Messenger-rna, Motor behavior, Mouse, Prp

How do metal cations affect the stability and structure of phospholipid bilayers? What role does ion binding play in the insertion of proteins and the overall mechanical stability of biological membranes? Investigators have used different theoretical and microscopic approaches to study the mechanical properties of lipid bilayers. Although they are crucial for such studies, molecular-dynamics simulations cannot yet span the complexity of biological membranes. In addition, there are still some experimental difficulties when it comes to testing the ion binding to lipid bilayers in an accurate way. Hence, there is a need to establish a new approach from the perspective of the nanometric scale, where most of the specific molecular phenomena take place. Atomic force microscopy has become an essential tool for examining the structure and behavior of lipid bilayers. In this work, we used force spectroscopy to quantitatively characterize nanomechanical resistance as a function of the electrolyte composition by means of a reliable molecular fingerprint that reveals itself as a repetitive jump in the approaching force curve. By systematically probing a set of bilayers of different composition immersed in electrolytes composed of a variety of monovalent and divalent metal cations, we were able to obtain a wealth of information showing that each ion makes an independent and important contribution to the gross mechanical resistance and its plastic properties. This work addresses the need to assess the effects of different ions on the structure of phospholipid membranes, and opens new avenues for characterizing the (nano)mechanical stability of membranes.

JTD Keywords: Molecular-dynamics simulation, Liquid expanded monolayers, Lipid-bilayers, Hofmeister series, Monovalent salt, Phosphatidylcholine, Microscopy, Binding, Surfaces, NaCl