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Dive into the research topics where John F. Wesseling is active.

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Featured researches published by John F. Wesseling.


Neuron | 2009

Downregulation of NR3A-Containing NMDARs Is Required for Synapse Maturation and Memory Consolidation

Adam C. Roberts; Javier Díez-García; Ramona M. Rodriguiz; Iciar P. López; Rafael Luján; Rebeca Martínez-Turrillas; Esther Picó; Maile A. Henson; Danilo R. Bernardo; Thomas M. Jarrett; Dallis J. Clendeninn; Laura López-Mascaraque; Guoping Feng; Donald C. Lo; John F. Wesseling; William C. Wetsel; Benjamin D. Philpot; Isabel Pérez-Otaño

NR3A is the only NMDA receptor (NMDAR) subunit that downregulates sharply prior to the onset of sensitive periods for plasticity, yet the functional importance of this transient expression remains unknown. To investigate whether removal/replacement of juvenile NR3A-containing NMDARs is involved in experience-driven synapse maturation, we used a reversible transgenic system that prolonged NR3A expression in the forebrain. We found that removal of NR3A is required to develop strong NMDAR currents, full expression of long-term synaptic plasticity, a mature synaptic organization characterized by more synapses and larger postsynaptic densities, and the ability to form long-term memories. Deficits associated with prolonged NR3A were reversible, as late-onset suppression of transgene expression rescued both synaptic and memory impairments. Our results suggest that NR3A behaves as a molecular brake to prevent the premature strengthening and stabilization of excitatory synapses and that NR3A removal might thereby initiate critical stages of synapse maturation during early postnatal neural development.


Nature Medicine | 2013

Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models

Sonia Marco; Albert Giralt; Milos M Petrovic; Mahmoud A. Pouladi; Rebeca Martínez-Turrillas; José Martínez-Hernández; Linda S. Kaltenbach; Jesús F. Torres-Peraza; Rona K. Graham; Masahiko Watanabe; Rafael Luján; Nobuki Nakanishi; Stuart A. Lipton; Donald C. Lo; Michael R. Hayden; Jordi Alberch; John F. Wesseling; Isabel Pérez-Otaño

Huntingtons disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntingtons disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntingtons disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntingtons disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntingtons disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression.


The Journal of Neuroscience | 2013

Tyrosine phosphorylation regulates the endocytosis and surface expression of GluN3A-containing NMDA receptors.

Dhrubajyoti Chowdhury; Sonia Marco; Ivan M. Brooks; Aitor Zandueta; Yijian Rao; Volker Haucke; John F. Wesseling; Steven J. Tavalin; Isabel Pérez-Otaño

Selective control of receptor trafficking provides a mechanism for remodeling the receptor composition of excitatory synapses, and thus supports synaptic transmission, plasticity, and development. GluN3A (formerly NR3A) is a nonconventional member of the NMDA receptor (NMDAR) subunit family, which endows NMDAR channels with low calcium permeability and reduced magnesium sensitivity compared with NMDARs comprising only GluN1 and GluN2 subunits. Because of these special properties, GluN3A subunits act as a molecular brake to limit the plasticity and maturation of excitatory synapses, pointing toward GluN3A removal as a critical step in the development of neuronal circuitry. However, the molecular signals mediating GluN3A endocytic removal remain unclear. Here we define a novel endocytic motif (YWL), which is located within the cytoplasmic C-terminal tail of GluN3A and mediates its binding to the clathrin adaptor AP2. Alanine mutations within the GluN3A endocytic motif inhibited clathrin-dependent internalization and led to accumulation of GluN3A-containing NMDARs at the cell surface, whereas mimicking phosphorylation of the tyrosine residue promoted internalization and reduced cell-surface expression as shown by immunocytochemical and electrophysiological approaches in recombinant systems and rat neurons in primary culture. We further demonstrate that the tyrosine residue is phosphorylated by Src family kinases, and that Src-activation limits surface GluN3A expression in neurons. Together, our results identify a new molecular signal for GluN3A internalization that couples the functional surface expression of GluN3A-containing receptors to the phosphorylation state of GluN3A subunits, and provides a molecular framework for the regulation of NMDAR subunit composition with implications for synaptic plasticity and neurodevelopment.


The Journal of Neuroscience | 2011

A New Kinetic Framework for Synaptic Vesicle Trafficking Tested in Synapsin Knock-Outs

Thomas Gabriel; Elizabeth Garcia-Perez; Kashif Mahfooz; Joaquín Goñi; Rebeca Martínez-Turrillas; Isabel Pérez-Otaño; Donald C. Lo; John F. Wesseling

At least two rate-limiting mechanisms in vesicle trafficking operate at mouse Schaffer collateral synapses, but their molecular/physical identities are unknown. The first mechanism determines the baseline rate at which reserve vesicles are supplied to a readily releasable pool. The second causes the supply rate to depress threefold when synaptic transmission is driven hard for extended periods. Previous models invoked depletion of a reserve vesicle pool to explain the reductions in the supply rate, but the mass-action assumption at their core is not compatible with kinetic measurements of neurotransmission under maximal-use conditions. Here we develop a new theoretical model of rate-limiting steps in vesicle trafficking that is compatible with previous and new measurements. A physical interpretation is proposed where local reserve pools consisting of four vesicles are tethered to individual release sites and are replenished stochastically in an all-or-none fashion. We then show that the supply rate depresses more rapidly in synapsin knock-outs and that the phenotype can be fully explained by changing the value of the single parameter in the model that would specify the size of the local reserve pools. Vesicle-trafficking rates between pools were not affected. Finally, optical imaging experiments argue against alternative interpretations of the theoretical model where vesicle trafficking is inhibited without reserve pool depletion. This new conceptual framework will be useful for distinguishing which of the multiple molecular and cell biological mechanisms involved in vesicle trafficking are rate limiting at different levels of synaptic throughput and are thus candidates for physiological and pharmacological modulation.


Journal of Neurophysiology | 2008

Augmentation Controls the Fast Rebound From Depression at Excitatory Hippocampal Synapses

Elizabeth Garcia-Perez; John F. Wesseling

Short-term plasticity occurs at most central chemical synapses and includes both positive and negative components, but the principles governing interaction between components are largely unknown. The residual Ca(2+) that persists in presynaptic terminals for several seconds after repetitive use is known to enhance neurotransmitter release under artificial, low probability of release conditions where depression is absent; this is termed augmentation. However, the full impact of augmentation under standard conditions at synapses where depression dominates is not known because of possibly complicated convolution with a variety of potential depression mechanisms. This report shows that residual Ca(2+) continues to have a large enhancing impact on release at excitatory hippocampal synapses recovering from depression, including when only recently recruited vesicles are available for release. No evidence was found for gradual vesicle priming or for fast refilling of a highly releasable subdivision of the readily releasable pool (RRP). And decay of enhancement matched the clearance of residual Ca(2+), thus matching the behavior of augmentation when studied in isolation. Because of incomplete RRP replenishment, synaptic strength was not typically increased above baseline when residual Ca(2+) levels were highest. Instead residual Ca(2+) caused single pulse release probability to rebound quickly from depression and then depress quickly during subsequent bursts of activity. Together, these observations can help resolve discrepancies in recent timing estimates of recovery from depression. Additionally, in contrast to results obtained under reduced release conditions, augmentation could be driven to a maximal level, occluding paired-pulse facilitation and other mechanisms that increase release efficiency.


Epilepsia | 2015

Levetiracetam accelerates the onset of supply rate depression in synaptic vesicle trafficking

Elizabeth Garcia-Perez; Kashif Mahfooz; João Covita; Aitor Zandueta; John F. Wesseling

To determine if levetiracetam (LEV) enhances the impact in excitatory presynaptic terminals of a rate‐limiting mechanism in vesicle trafficking termed supply rate depression that emerges to limit synaptic transmission during heavy, epileptiform use.


JAMA Neurology | 2015

Modulation of GluN3A expression in Huntington disease: a new n-methyl-D-aspartate receptor-based therapeutic approach?

John F. Wesseling; Isabel Pérez-Otaño

Huntington disease (HD) is an inherited neurodegenerative disorder with no cure or effective palliative treatment. An ideal therapy would arrest pathogenesis at early stages before neuronal damage occurs. However, although the genetic mutation that causes HD is known, the molecular chain of events that leads from the mutation to disease is not well understood. Accumulating evidence suggests that synaptic dysregulation may be involved, and the earliest known deficit is hyperfunction of glutamate-type N-methyl-d-aspartate receptors (NMDARs) in the selectively vulnerable medium spiny neurons of the striatum. A previous study found that the mutant Htt protein interferes with downregulation of juvenile NMDAR subtypes that contain GluN3A subunits by sequestering the endocytic adaptor PACSIN1 and preventing their removal from the cell surface. Loss of PACSIN1 and consequent gain of GluN3A function reactivate a synapse pruning mechanism that is important during development but harmful when active at later stages. Suppressing the GluN3A reactivation corrected the NMDAR hyperfunction and prevented the full range of HD signs and symptoms in mouse models, encouraging efforts to develop GluN3A-selective antagonists and/or explore alternative therapeutic approaches to block GluN3A expression.


PLOS Computational Biology | 2016

A Well-Defined Readily Releasable Pool with Fixed Capacity for Storing Vesicles at Calyx of Held.

Kashif Mahfooz; Mahendra Singh; Robert Renden; John F. Wesseling

The readily releasable pool (RRP) of vesicles is a core concept in studies of presynaptic function. However, operating principles lack consensus definition and the utility for quantitative analysis has been questioned. Here we confirm that RRPs at calyces of Held from 14 to 21 day old mice have a fixed capacity for storing vesicles that is not modulated by Ca2+. Discrepancies with previous studies are explained by a dynamic flow-through pool, established during heavy use, containing vesicles that are released with low probability despite being immediately releasable. Quantitative analysis ruled out a posteriori explanations for the vesicles with low release probability, such as Ca2+-channel inactivation, and established unexpected boundary conditions for remaining alternatives. Vesicles in the flow-through pool could be incompletely primed, in which case the full sequence of priming steps downstream of recruitment to the RRP would have an average unitary rate of at least 9/s during heavy use. Alternatively, vesicles with low and high release probability could be recruited to distinct types of release sites; in this case the timing of recruitment would be similar at the two types, and the downstream transition from recruited to fully primed would be much faster. In either case, further analysis showed that activity accelerates the upstream step where vesicles are initially recruited to the RRP. Overall, our results show that the RRP can be well defined in the mathematical sense, and support the concept that the defining mechanism is a stable group of autonomous release sites.


The Journal of Neuroscience | 2002

Limit on the role of activity in controlling the release-ready supply of synaptic vesicles

John F. Wesseling; Donald C. Lo


Nature Reviews Neuroscience | 2016

Emerging roles of GluN3-containing NMDA receptors in the CNS

Isabel Pérez-Otaño; Rylan S. Larsen; John F. Wesseling

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Sonia Marco

University of Barcelona

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