Hebb and the art of spine remodeling

The notion that synaptic remodeling underlies certain forms of learning is one of the main tenets of Hebb's inspiring theories dating from the 1940s. Until recently, however, direct evidence for tight relationships between synaptic remodeling and behavior has been scarce. Fascinating data from recent studies on the remodeling of postsynaptic structures known as dendritic spines indicates that such relationships might be more complex than initially expected

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies

A pre-registered, multi-lab non-replication of the Action-sentence Compatibility Effect (ACE)

The Action-sentence Compatibility Effect (ACE) is a well-known demonstration of the role of motor activity in the comprehension of language. Participants are asked to make sensibility judgments on sentences by producing movements toward the body or away from the body. The ACE is the finding that movements are faster when the direction of the movement (e.g., toward) matches the direction of the action in the to-be-judged sentence (e.g., Art gave you the pen describes action toward you). We report on a pre-registered, multi-lab replication of one version of the ACE. The results show that none of the 18 labs involved in the study observed a reliable ACE, and that the meta-analytic estimate of the size of the ACE was essentially zero.Fil: Morey, Richard. Cardiff University; Reino UnidoFil: Kaschak, Michael. Florida State University; Estados UnidosFil: Díez Álamo, Antonio. Universidad de Salamanca; España. Arizona State University; Estados UnidosFil: Glenberg, Arthur. Arizona State University; Estados Unidos. Universidad de Salamanca; EspañaFil: Zwaan, Rolf A.. Erasmus University Rotterdam; Países BajosFil: Lakens, Daniël. Eindhoven University of Technology; Países BajosFil: Ibáñez, Santiago Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. University of San Francisco; Estados Unidos. Universidad Adolfo Ibañez; Chile. Trinity College Dublin; IrlandaFil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de San Andrés; Argentina. University of San Francisco; Estados Unidos. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; Argentina. Universidad de Santiago de Chile; ChileFil: Gianelli, Claudia. Universitat Potsdam; Alemania. Scuola Universitaria Superiore; ItaliaFil: Jones, John L.. Florida State University; Estados UnidosFil: Madden, Julie. University of Tennessee; Estados UnidosFil: Alifano Ferrero, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bergen, Benjamin. University of California at San Diego; Estados UnidosFil: Bloxsom, Nicholas G.. Ashland University; Estados UnidosFil: Bub, Daniel N.. University of Victoria; CanadáFil: Cai, Zhenguang G.. The Chinese University; Hong KongFil: Chartier, Christopher R.. Ashland University; Estados UnidosFil: Chatterjee, Anjan. University of Pennsylvania; Estados UnidosFil: Conwell, Erin. North Dakota State University; Estados UnidosFil: Wagner Cook, Susan. University of Iowa; Estados UnidosFil: Davis, Joshua D.. University of California at San Diego; Estados UnidosFil: Evers, Ellen R. K.. University of California at Berkeley; Estados UnidosFil: Girard, Sandrine. University of Carnegie Mellon; Estados UnidosFil: Harter, Derek. Texas A&m University Commerce; Estados UnidosFil: Hartung, Franziska. University of Pennsylvania; Estados UnidosFil: Herrera, Eduar. Universidad ICESI; ColombiaFil: Huettig, Falk. Max Planck Institute for Psycholinguistics; Países BajosFil: Humphries, Stacey. University of Pennsylvania; Estados UnidosFil: Juanchich, Marie. University of Essex; Reino UnidoFil: Kühne, Katharina. Universitat Potsdam; AlemaniaFil: Lu, Shulan. Texas A&m University Commerce; Estados UnidosFil: Lynes, Tom. University of East Anglia; Reino UnidoFil: Masson, Michael E. J.. University of Victoria; CanadáFil: Ostarek, Markus. Max Planck Institute for Psycholinguistics; Países BajosFil: Pessers, Sebastiaan. Katholikie Universiteit Leuven; BélgicaFil: Reglin, Rebecca. Universitat Potsdam; AlemaniaFil: Steegen, Sara. Katholikie Universiteit Leuven; BélgicaFil: Thiessen, Erik D.. University of Carnegie Mellon; Estados UnidosFil: Thomas, Laura E.. North Dakota State University; Estados UnidosFil: Trott, Sean. University of California at San Diego; Estados UnidosFil: Vandekerckhove, Joachim. University of California at Irvine; Estados UnidosFil: Vanpaeme, Wolf. Katholikie Universiteit Leuven; BélgicaFil: Vlachou, Maria. Katholikie Universiteit Leuven; BélgicaFil: Williams, Kristina. Texas A&m University Commerce; Estados UnidosFil: Ziv Crispel, Noam. BehavioralSight; Estados Unido

Negative Regulation of Active Zone Assembly by a Newly Identified SR Protein Kinase

A neuronal serine-arginine protein kinase that localizes to the presynaptic active zone is required for kinase-dependent repression of active zone assembly

Long-Term Relationships between Synaptic Tenacity, Synaptic Remodeling, and Network Activity

Long term time-lapse imaging reveals that individual synapses undergo significant structural remodeling not only when driven by activity, but also when network activity is absent, raising questions about how reliably individual synapses maintain connections

Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non-Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2-5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load synaptic protein turnover places on individual neurons is very substantial

Closed Loop Experiment Manager (CLEM)—An Open and Inexpensive Solution for Multichannel Electrophysiological Recordings and Closed Loop Experiments

There is growing need for multichannel electrophysiological systems that record from and interact with neuronal systems in near real-time. Such systems are needed, for example, for closed loop, multichannel electrophysiological/optogenetic experimentation in vivo and in a variety of other neuronal preparations, or for developing and testing neuro-prosthetic devices, to name a few. Furthermore, there is a need for such systems to be inexpensive, reliable, user friendly, easy to set-up, open and expandable, and possess long life cycles in face of rapidly changing computing environments. Finally, they should provide powerful, yet reasonably easy to implement facilities for developing closed-loop protocols for interacting with neuronal systems. Here, we survey commercial and open source systems that address these needs to varying degrees. We then present our own solution, which we refer to as Closed Loop Experiments Manager (CLEM). CLEM is an open source, soft real-time, Microsoft Windows desktop application that is based on a single generic personal computer (PC) and an inexpensive, general-purpose data acquisition board. CLEM provides a fully functional, user-friendly graphical interface, possesses facilities for recording, presenting and logging electrophysiological data from up to 64 analog channels, and facilities for controlling external devices, such as stimulators, through digital and analog interfaces. Importantly, it includes facilities for running closed-loop protocols written in any programming language that can generate dynamic link libraries (DLLs). We describe the application, its architecture and facilities. We then demonstrate, using networks of cortical neurons growing on multielectrode arrays (MEA) that despite its reliance on generic hardware, its performance is appropriate for flexible, closed-loop experimentation at the neuronal network level

Recent insights on principles of synaptic protein degradation [version 1; referees: 3 approved]

Maintaining synaptic integrity and function depends on the continuous removal and degradation of aged or damaged proteins. Synaptic protein degradation has received considerable attention in the context of synaptic plasticity and growing interest in relation to neurodegenerative and other disorders. Conversely, less attention has been given to constitutive, ongoing synaptic protein degradation and the roles canonical degradation pathways play in these processes. Here we briefly review recent progress on this topic and new experimental approaches which have expedited such progress and highlight several emerging principles. These include the realization that synaptic proteins typically have unusually long lifetimes, as might be expected from the remote locations of most synaptic sites; the possibility that degradation pathways can change with time from synthesis, cellular context, and physiological input; and that degradation pathways, other than ubiquitin-proteasomal-mediated degradation, might play key roles in constitutive protein degradation at synaptic sites. Finally, we point to the importance of careful experimental design and sufficiently sensitive techniques for studying synaptic protein degradation, which bring into account their slow turnover rates and complex life cycles