Publications by authors named "José A Esteban"

56 Publications

Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation.

Sci Signal 2021 Feb 16;14(670). Epub 2021 Feb 16.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.

The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor-dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.
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http://dx.doi.org/10.1126/scisignal.abb1953DOI Listing
February 2021

GSK3α, not GSK3β, drives hippocampal NMDAR-dependent LTD via tau-mediated spine anchoring.

EMBO J 2021 Jan 16;40(2):e105513. Epub 2020 Nov 16.

Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, Madrid, Spain.

Glycogen synthase kinase-3 (GSK3) is an important signalling protein in the brain and modulates different forms of synaptic plasticity. Neuronal functions of GSK3 are typically attributed to one of its two isoforms, GSK3β, simply because of its prevalent expression in the brain. Consequently, the importance of isoform-specific functions of GSK3 in synaptic plasticity has not been fully explored. We now directly address this question for NMDA receptor-dependent long-term depression (LTD) in the hippocampus. Here, we specifically target the GSK3 isoforms with shRNA knock-down in mouse hippocampus and with novel isoform-selective drugs to dissect their roles in LTD. Using electrophysiological and live imaging approaches, we find that GSK3α, but not GSK3β, is required for LTD. The specific engagement of GSK3α occurs via its transient anchoring in dendritic spines during LTD induction. We find that the major GSK3 substrate, the microtubule-binding protein tau, is required for this spine anchoring of GSK3α and mediates GSK3α-induced LTD. These results link GSK3α and tau in a common mechanism for synaptic depression and rule out a major role for GSK3β in this process.
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http://dx.doi.org/10.15252/embj.2020105513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809792PMC
January 2021

A retention-release mechanism based on RAB11FIP2 for AMPA receptor synaptic delivery during long-term potentiation.

J Cell Sci 2019 12 16;132(24). Epub 2019 Dec 16.

Department of Neurobiology, Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), 28049 Madrid, Spain

It is well--established that Rab11-dependent recycling endosomes drive the activity-dependent delivery of AMPA receptors (AMPARs) into synapses during long-term potentiation (LTP). Nevertheless, the molecular basis for this specialized function of recycling endosomes is still unknown. Here, we have investigated RAB11FIP2 (FIP2 hereafter) as a potential effector of Rab11-dependent trafficking during LTP in rat hippocampal slices. Surprisingly, we found that FIP2 operates independently from Rab11 proteins, and acts as a negative regulator of AMPAR synaptic trafficking. Under basal conditions, FIP2 associates with AMPARs at immobile compartments, separately from recycling endosomes. Using shRNA-mediated knockdown, we found that FIP2 prevents GluA1 (encoded by the gene) AMPARs from reaching the surface of dendritic spines in the absence of neuronal stimulation. Upon induction of LTP, FIP2 is rapidly mobilized, dissociates from AMPARs and undergoes dephosphorylation. Interestingly, this dissociation of the FIP2-AMPAR complex, together with FIP2 dephosphorylation, is required for LTP, but the interaction between FIP2 and Rab11 proteins is not. Based on these results, we propose a retention-release mechanism, where FIP2 acts as a gate that restricts the trafficking of AMPARs, until LTP induction triggers their release and allows synaptic delivery.
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http://dx.doi.org/10.1242/jcs.234237DOI Listing
December 2019

Corrigendum to: -PTEN activity defines an axis for plasticity at cortico-amygdala synapses and influences social behavior.

Cereb Cortex 2020 03;30(2):849

Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain.

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http://dx.doi.org/10.1093/cercor/bhz232DOI Listing
March 2020

NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation.

EMBO Rep 2019 11 18;20(11):e48143. Epub 2019 Sep 18.

Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain.

NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients.
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http://dx.doi.org/10.15252/embr.201948143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832102PMC
November 2019

Inhibition of p38 MAPK in the brain through nasal administration of p38 inhibitor loaded in chitosan nanocapsules.

Nanomedicine (Lond) 2019 09 28;14(18):2409-2422. Epub 2019 Aug 28.

Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, 28049 Madrid, Spain.

To determine whether a p38 MAPK inhibitor incorporated into nanoemulsion-based chitosan nanocapsules can reduce the activity of this kinase in the brain through their nasal administration in mice. We selected the p38 MAPK inhibitor PH797804, an ATP-competitive inhibitor of p38α encapsulated in nanoemulsion-based chitosan nanocapsules. Biological effect was evaluated in microglial and neuronal cells and in and systems, in a mouse model of Alzheimer's disease. Encapsulated inhibitor retains enzymatic inhibitory activity and tissue penetration capacity and . Nasal administration of chitosan nanocapsules can be an effective approach for brain-restricted reduction of p38 MAPK activity, thus reducing the side effects of systemic administration.
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http://dx.doi.org/10.2217/nnm-2018-0496DOI Listing
September 2019

Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer's disease pathogenesis.

Nat Neurosci 2019 08 15;22(8):1258-1268. Epub 2019 Jul 15.

Centro de Biología Molecular 'Severo Ochoa', CSIC-UAM, Universidad Autónoma de Madrid, Madrid, Spain.

The deposition of aggregated amyloid-β peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer's disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-β formation. We tested whether downregulation of ADAM10 activity by its secreted endogenous inhibitor secreted-frizzled-related protein 1 (SFRP1) is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of patients with AD, accumulates in APs and binds to amyloid-β, hindering amyloid-β protofibril formation. Sfrp1 overexpression in an AD-like mouse model anticipates the appearance of APs and dystrophic neurites, whereas its genetic inactivation or the infusion of α-SFRP1-neutralizing antibodies favors non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents long-term potentiation loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target.
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http://dx.doi.org/10.1038/s41593-019-0432-1DOI Listing
August 2019

Astrocytic p38α MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory.

Nat Commun 2019 07 4;10(1):2968. Epub 2019 Jul 4.

Department of Neurobiology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain.

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.
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http://dx.doi.org/10.1038/s41467-019-10830-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609681PMC
July 2019

PTEN Activity Defines an Axis for Plasticity at Cortico-Amygdala Synapses and Influences Social Behavior.

Cereb Cortex 2020 03;30(2):505-524

Molecular Cognition Laboratory, Biophysics Institute, Consejo Superior de Investigaciones Cientificas (CSIC)-University of the Basque Country (UPV)/Euskal Herriko University (EHU), Campus Universidad del País Vasco, 48940 Leioa, Spain.

Phosphatase and tensin homolog on chromosome 10 (PTEN) is a tumor suppressor and autism-associated gene that exerts an important influence over neuronal structure and function during development. In addition, it participates in synaptic plasticity processes in adulthood. As an attempt to assess synaptic and developmental mechanisms by which PTEN can modulate cognitive function, we studied the consequences of 2 different genetic manipulations in mice: presence of additional genomic copies of the Pten gene (Ptentg) and knock-in of a truncated Pten gene lacking its PDZ motif (Pten-ΔPDZ), which is required for interaction with synaptic proteins. Ptentg mice exhibit substantial microcephaly, structural hypoconnectivity, enhanced synaptic depression at cortico-amygdala synapses, reduced anxiety, and intensified social interactions. In contrast, Pten-ΔPDZ mice have a much more restricted phenotype, with normal synaptic connectivity, but impaired synaptic depression at cortico-amygdala synapses and virtually abolished social interactions. These results suggest that synaptic actions of PTEN in the amygdala contribute to specific behavioral traits, such as sociability. Also, PTEN appears to function as a bidirectional rheostat in the amygdala: reduction in PTEN activity at synapses is associated with less sociability, whereas enhanced PTEN activity accompanies hypersocial behavior.
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http://dx.doi.org/10.1093/cercor/bhz103DOI Listing
March 2020

Store-Operated Calcium Entry Is Required for mGluR-Dependent Long Term Depression in Cortical Neurons.

Front Cell Neurosci 2017 14;11:363. Epub 2017 Dec 14.

Department of Molecular Biology, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.

Store-operated calcium entry (SOCE) is a Calcium (Ca) influx pathway activated by depletion of intracellular stores that occurs in eukaryotic cells. In neurons, the presence and functions of SOCE are still in question. Here, we show evidences for the existence of SOCE in primary mouse cortical neurons. Endoplasmic reticulum (ER)-Ca depletion using thapsigargin (Tg) triggered a maintained cytosolic Ca increase, which rapidly returned to basal level in the presence of the SOCE blockers 2-Aminoethoxydiphenyl borate (2-APB) and YM-58483. Neural SOCE is also engaged by activation of metabotropic glutamate receptors (mGluRs) with (S)-3,5-dihydroxyphenylglycine (DHPG) (agonist of group I mGluRs), being an essential mechanism to maintain the mGluR-driven Ca signal. Activation of group I of mGluRs triggers long-term depression (LTD) in many brain regions, but the underlying mechanism and, specifically, the necessity of Ca increase in the postsynaptic neuron is controversial. In primary cortical neurons, we now show that the inhibition of Ca influx through SOCE impaired DHPG-LTD, pointing out a key function of calcium and SOCE in synaptic plasticity.
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http://dx.doi.org/10.3389/fncel.2017.00363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735122PMC
December 2017

Building Bridges through Science.

Authors:
Thomas Lissek Michelle Adams John Adelman Ehud Ahissar Mohammed Akaaboune Huda Akil Mustafa al'Absi Fazal Arain Juan Carlos Arango-Lasprilla Deniz Atasoy Jesus Avila Ashraf Badawi Hilmar Bading Abdul Mannan Baig Jimena Baleriola Carlos Belmonte Ilaria Bertocchi Heinrich Betz Colin Blakemore Olaf Blanke Philipp Boehm-Sturm Tobias Bonhoeffer Paolo Bonifazi Nils Brose Patrizia Campolongo Tansu Celikel Cathy C Chang Ta-Yuan Chang Ami Citri Hollis T Cline Jesus M Cortes Kathleen Cullen Kellie Dean José M Delgado-Garcia Mathieu Desroches John F Disterhoft John E Dowling Andreas Draguhn Sherif F El-Khamisy Abdeljabbar El Manira S Ather Enam Juan M Encinas Asier Erramuzpe José A Esteban Isabel Fariñas Edmond Fischer Izumi Fukunaga Iñigo Gabilondo Detlev Ganten Albert Gidon Juan Carlos Gomez-Esteban Paul Greengard Valery Grinevich Agnés Gruart Roger Guillemin Ahmad R Hariri Bassem Hassan Michael Häusser Yasunori Hayashi Natasha K Hussain Adnan Abdul Jabbar Mohamed Jaber Reinhardt Jahn Essam Mohammed Janahi Mohamed Kabbaj Helmut Kettenmann Merel Kindt Shira Knafo Georg Köhr Shoji Komai Harm Krugers Bernd Kuhn Nouria Lakhdar Ghazal Matthew E Larkum Mickey London Beat Lutz Carlos Matute Luis Martinez-Millan Mouna Maroun James McGaugh Ahmed A Moustafa Anwar Nasim Klaus-Armin Nave Erwin Neher Karoly Nikolich Tiago Outeiro Lucy M Palmer Olga Penagarikano Isabel Perez-Otano Donald W Pfaff Bruno Poucet Atta-Ur Rahman Pedro Ramos-Cabrer Ali Rashidy-Pour Richard J Roberts Serafim Rodrigues Joshua R Sanes Andreas T Schaefer Menahem Segal Idan Segev Saad Shafqat Nikhat Ahmed Siddiqui Hermona Soreq Eduardo Soriano-García Rainer Spanagel Rolf Sprengel Greg Stuart Thomas C Südhof Jan Tønnesen Mario Treviño Basim M Uthman J Craig Venter Alexei Verkhratsky Craig Weiss Torsten N Wiesel Emre Yaksi Ofer Yizhar Larry J Young Paul Young Nasser H Zawia José L Zugaza Mazahir T Hasan

Neuron 2017 Nov;96(4):730-735

Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain. Electronic address:

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.
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http://dx.doi.org/10.1016/j.neuron.2017.09.028DOI Listing
November 2017

MAP1B Light Chain Modulates Synaptic Transmission via AMPA Receptor Intracellular Trapping.

J Neurosci 2017 10 13;37(41):9945-9963. Epub 2017 Sep 13.

Department of Neurobiology, Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), Madrid 28049, Spain, and

The regulated transport of AMPA-type glutamate receptors (AMPARs) to the synaptic membrane is a key mechanism to determine the strength of excitatory synaptic transmission in the brain. In this work, we uncovered a new role for the microtubule-associated protein MAP1B in modulating access of AMPARs to the postsynaptic membrane. Using mice and rats of either sex, we show that MAP1B light chain (LC) accumulates in the somatodendritic compartment of hippocampal neurons, where it forms immobile complexes on microtubules that limit vesicular transport. These complexes restrict AMPAR dendritic mobility, leading to the intracellular trapping of receptors and impairing their access to the dendritic surface and spines. Accordingly, increasing MAP1B-LC expression depresses AMPAR-mediated synaptic transmission. This effect is specific for the GluA2 subunit of the AMPAR and requires glutamate receptor interacting protein 1 (GRIP1) interaction with MAP1B-LC. Therefore, MAP1B-LC represents an alternative link between GRIP1-AMPARs and microtubules that does not result in productive transport, but rather limits AMPAR availability for synaptic insertion, with a direct impact on synaptic transmission. The ability of neurons to modify their synaptic connections, known as synaptic plasticity, is accepted as the cellular basis for learning and memory. One mechanism for synaptic plasticity is the regulated addition and removal of AMPA-type glutamate receptors (AMPARs) at excitatory synapses. In this study, we found that a microtubule-associated protein, MAP1B light chain (MAP1B-LC), participates in this process. MAP1B-LC forms immobile complexes along dendrites. These complexes limit intracellular vesicular trafficking and trap AMPARs inside the dendritic shaft. In this manner, MAP1B restricts the access of AMPARs to dendritic spines and the postsynaptic membrane, contributing to downregulating synaptic transmission.
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http://dx.doi.org/10.1523/JNEUROSCI.0505-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596595PMC
October 2017

Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling β-amyloid production.

Sci Rep 2017 03 31;7:45306. Epub 2017 Mar 31.

Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α∆-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α∆-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.
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http://dx.doi.org/10.1038/srep45306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374488PMC
March 2017

In Utero Electroporation Approaches to Study the Excitability of Neuronal Subpopulations and Single-cell Connectivity.

J Vis Exp 2017 02 15(120). Epub 2017 Feb 15.

Department for Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB-CSIC);

The nervous system is composed of an enormous range of distinct neuronal types. These neuronal subpopulations are characterized by, among other features, their distinct dendritic morphologies, their specific patterns of axonal connectivity, and their selective firing responses. The molecular and cellular mechanisms responsible for these aspects of differentiation during development are still poorly understood. Here, we describe combined protocols for labeling and characterizing the structural connectivity and excitability of cortical neurons. Modification of the in utero electroporation (IUE) protocol allows the labeling of a sparse population of neurons. This, in turn, enables the identification and tracking of the dendrites and axons of individual neurons, the precise characterization of the laminar location of axonal projections, and morphometric analysis. IUE can also be used to investigate changes in the excitability of wild-type (WT) or genetically modified neurons by combining it with whole-cell recording from acute slices of electroporated brains. These two techniques contribute to a better understanding of the coupling of structural and functional connectivity and of the molecular mechanisms controlling neuronal diversity during development. These developmental processes have important implications on axonal wiring, the functional diversity of neurons, and the biology of cognitive disorders.
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http://dx.doi.org/10.3791/55139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409320PMC
February 2017

Tetraspanin 6: A novel regulator of hippocampal synaptic transmission and long term plasticity.

PLoS One 2017 16;12(2):e0171968. Epub 2017 Feb 16.

Centro de Biologıa Molecular 'Severo Ochoa' (CSIC/UAM), Madrid, Spain.

Tetraspanins (Tspan) are transmembrane proteins with important scaffold and signalling functions. Deletions of Tetraspanin 6 (Tspan6) gene, a member of the tetraspanin family, have been reported in patients with Epilepsy Female-restricted with Mental Retardation (EFMR). Interestingly, mutations in Tspan7, highly homologous to Tspan6, are associated with X-linked intellectual disability, suggesting that these two proteins are important for cognition. Considering recent evidences showing that Tspan7 plays a key role in synapse development and AMPAR trafficking, we initiated the study of Tspan6 in synaptic function using a Tspan6 knock out mouse model. Here we report that hippocampal field recordings from Tspan6 knock out mice show an enhanced basal synaptic transmission and impaired long term potentiation (LTP). A normal paired-pulse facilitation response suggests that Tspan6 affects the properties of the postsynaptic rather than the presynaptic terminal. However, no changes in spine morphology or postsynaptic markers could be detected in Tspan6 KO mice compared with wild types. In addition, Tspan6 KO mice show normal locomotor behaviour and no defects in hippocampus-dependent memory tests.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312877PMC
August 2017

PTEN: Local and Global Modulation of Neuronal Function in Health and Disease.

Trends Neurosci 2017 02 10;40(2):83-91. Epub 2017 Jan 10.

Department of Molecular Neurobiology, Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid, 28049 Madrid, Spain. Electronic address:

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) was recently revealed to be a synaptic player during plasticity events in addition to its well-established role as a general controlling factor in cell proliferation and neuronal growth during development. Alterations of these direct actions of PTEN at synapses may lead to synaptic dysfunction with behavioral and cognitive consequences. A recent paradigmatic example of this situation, Alzheimer's disease (AD), is associated with excessive recruitment of PTEN into synapses leading to pathological synaptic depression. By contrast, some forms of autism are characterized by failure to weaken synaptic connections, which may be related to insufficient PTEN signaling. Understanding the modulation of synaptic function by PTEN in these pathologies may contribute to the development of new therapies.
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http://dx.doi.org/10.1016/j.tins.2016.11.008DOI Listing
February 2017

A diet enriched with plant sterols prevents the memory impairment induced by cholesterol loss in senescence-accelerated mice.

Neurobiol Aging 2016 12 20;48:1-12. Epub 2016 Aug 20.

Centro Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain. Electronic address:

Cholesterol reduction at the neuronal plasma membrane has been related to age-dependent cognitive decline. We have used senescent-accelerated mice strain 8 (SAMP8), an animal model for aging, to examine the association between cholesterol loss and cognitive impairment and to test strategies to revert this process. We show that the hippocampus of SAMP8 mice presents reduced cholesterol levels and enhanced amount of its degrading enzyme Cyp46A1 (Cyp46) already at 6 months of age. Cholesterol loss accounts for the impaired long-term potentiation in these mice. Plant sterol (PSE)-enriched diet prevents long-term potentiation impairment and cognitive deficits in SAMP8 mice without altering cholesterol levels. PSE diet also reduces the abnormally high amyloid peptide levels in SAMP8 mice brains and restores membrane compartmentalization of presenilin1, the catalytic component of the amyloidogenic γ-secretase. These results highlight the influence of cholesterol loss in age-related cognitive decline and provide with a noninvasive strategy to counteract it. Our results suggest that PSE overtake cholesterol functions in the brain contributing to reduce deleterious consequences of cholesterol loss during aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.08.009DOI Listing
December 2016

APPL1 gates long-term potentiation through its plekstrin homology domain.

J Cell Sci 2016 07 2;129(14):2793-803. Epub 2016 Jun 2.

Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid (CSIC-UAM), Madrid 28049, Spain

Hippocampal synaptic plasticity involves both membrane trafficking events and intracellular signaling, but how these are coordinated is far from clear. The endosomal transport of glutamate receptors in and out of the postsynaptic membrane responds to multiple signaling cascades triggered by synaptic activity. In this work, we have identified adaptor protein containing a plekstrin homology domain, phosphotyrosine-binding domain and leucine zipper motif 1 (APPL1) as a crucial element linking trafficking and signaling during synaptic plasticity. We show that APPL1 knockdown specifically impairs PI3K-dependent forms of synaptic plasticity, such as long-term potentiation (LTP) and metabotropic-glutamate-receptor-dependent long-term depression (mGluR-LTD). Indeed, we demonstrate that APPL1 is required for the activation of the phosphatidylinositol triphosphate (PIP3) pathway in response to LTP induction. This requirement can be bypassed by membrane localization of PI3K and is related to phosphoinositide binding. Interestingly, inhibitors of PDK1 (also known as PDPK1) and Akt have no effect on LTP expression. Therefore, we conclude that APPL1 gates PI3K activation at the plasma membrane upon LTP induction, which is then relayed by downstream PIP3 effectors that are different from PDK1 and Akt.
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http://dx.doi.org/10.1242/jcs.183475DOI Listing
July 2016

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis.

EMBO J 2016 07 19;35(13):1417-36. Epub 2016 May 19.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain

Tau is a microtubule-associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress-induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau(-/-) mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau(-/-) mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.
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http://dx.doi.org/10.15252/embj.201593518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876034PMC
July 2016

Administration of the TrkB receptor agonist 7,8-dihydroxyflavone prevents traumatic stress-induced spatial memory deficits and changes in synaptic plasticity.

Hippocampus 2016 09 21;26(9):1179-88. Epub 2016 Apr 21.

Unitat De Fisiologia Animal (Facultat De Biociències), Universitat Autònoma De Barcelona, 08193 Bellaterra, Barcelona, Spain.

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hipo.22599DOI Listing
September 2016

Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing.

Neuron 2016 Feb 21;89(3):494-506. Epub 2016 Jan 21.

Centro Nacional de Biotecnología (CNB-CSIC), Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain. Electronic address:

Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode. Loss of Cux1 function led to a decrease in the expression of Kv1 transcripts, aberrant firing responses, and selective loss of CC contralateral innervation. Firing and innervation were rescued by re-expression of Kv1 or postnatal reactivation of Cux1. Knocking down Kv1 mimicked Cux1-mediated CC axonal loss. These findings reveal that activity-dependent processes are central bona fide components of neuronal TF-differentiation programs and establish the importance of intrinsic firing modes in circuit assembly within the neocortex.
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http://dx.doi.org/10.1016/j.neuron.2015.12.020DOI Listing
February 2016

PTEN recruitment controls synaptic and cognitive function in Alzheimer's models.

Nat Neurosci 2016 Mar 18;19(3):443-53. Epub 2016 Jan 18.

Department of Molecular Neurobiology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC) / Universidad Autónoma de Madrid, Madrid, Spain.

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aβ-induced depression. Mechanistically, Aβ triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aβ-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aβ-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aβ signaling.
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http://dx.doi.org/10.1038/nn.4225DOI Listing
March 2016

The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.

Nat Commun 2015 Mar 18;6:6504. Epub 2015 Mar 18.

Dulbecco Telethon Institute at IRCCS San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milan, Italy.

RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). The role of AMPARs in synaptic transmission varies depending on the combination of subunits (GluA1, GluA2 and GluA3) they incorporate. RAB39B downregulation in mouse hippocampal neurons skews AMPAR composition towards non GluA2-containing Ca(2+)-permeable forms and thereby alters synaptic activity, specifically in hippocampal neurons. We posit that the resulting alteration in synaptic function underlies cognitive dysfunction in RAB39B-related disorders.
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http://dx.doi.org/10.1038/ncomms7504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383008PMC
March 2015

LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery.

J Cell Biol 2015 Mar 9;208(6):791-806. Epub 2015 Mar 9.

Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain

Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). We found that N-methyl-d-aspartate-type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron. A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation. This process is accompanied by an increase of NMDAR function and an enhancement of LTP. These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP.
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http://dx.doi.org/10.1083/jcb.201407122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362467PMC
March 2015

Mitochondrial ATP-Mg/Pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons.

J Neurosci 2015 Feb;35(8):3566-81

Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and

Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca(2+) and Na(+) influx, activation of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca(2+) deregulation. Mitochondria undergo early changes in membrane potential during excitotoxicity, but their precise role in these events is still controversial. Using primary cortical neurons derived from mice, we show that NMDA exposure results in a rapid fall in mitochondrial ATP in neurons deficient in SCaMC-3/Slc25a23, a Ca(2+)-regulated mitochondrial ATP-Mg/Pi carrier. This fall is associated with blunted increases in respiration and a delayed decrease in cytosolic ATP levels, which are prevented by PARP-1 inhibitors or by SCaMC-3 activity promoting adenine nucleotide uptake into mitochondria. SCaMC-3 KO neurons show an earlier delayed Ca(2+) deregulation, and SCaMC-3-deficient mitochondria incubated with ADP or ATP-Mg had reduced Ca(2+) retention capacity, suggesting a failure to maintain matrix adenine nucleotides as a cause for premature delayed Ca(2+) deregulation. SCaMC-3 KO neurons have higher vulnerability to in vitro excitotoxicity, and SCaMC-3 KO mice are more susceptible to kainate-induced seizures, showing that early PARP-1-dependent fall in mitochondrial ATP levels, counteracted by SCaMC-3, is an early step in the excitotoxic cascade.
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http://dx.doi.org/10.1523/JNEUROSCI.2702-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605552PMC
February 2015

PTEN counteracts PIP3 upregulation in spines during NMDA-receptor-dependent long-term depression.

J Cell Sci 2014 Dec 21;127(Pt 24):5253-60. Epub 2014 Oct 21.

Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM), Madrid 28049, Spain

Phosphoinositide 3-kinase (PI3K) and PTEN have been shown to participate in synaptic plasticity during long-term potentiation (LTP) and long-term depression (LTD), respectively. Nevertheless, the dynamics of phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) and the regulation of its synthesis and degradation at synaptic compartments is far from clear. Here, we have used fluorescence resonance energy transfer (FRET) imaging to monitor changes in PIP3 levels in dendritic spines from CA1 hippocampal neurons under basal conditions and upon induction of NMDA receptor (NMDAR)-dependent LTD and LTP. We found that PIP3 undergoes constant turnover in dendritic spines. Contrary to expectations, both LTD and LTP induction trigger an increase in PIP3 synthesis, which requires NMDARs and PI3K activity. Using biochemical methods, the upregulation of PIP3 levels during LTP was estimated to be twofold. However, in the case of LTD, PTEN activity counteracts the increase in PIP3 synthesis, resulting in no net change in PIP3 levels. Therefore, both LTP and LTD signaling converge towards PIP3 upregulation, but PTEN acts as an LTD-selective switch that determines the outcome of PIP3 accumulation.
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http://dx.doi.org/10.1242/jcs.156554DOI Listing
December 2014

Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus.

Proc Natl Acad Sci U S A 2014 Jan 23;111(1):E149-58. Epub 2013 Dec 23.

Center for Neuroscience and Cell Biology and Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.

Ghrelin is a peptide mainly produced by the stomach and released into circulation, affecting energy balance and growth hormone release. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary. However, GHS-R1a is expressed in other brain regions, including the hippocampus, where its activation enhances memory retention. Herein we explore the molecular mechanism underlying the action of ghrelin on hippocampal-dependent memory. Our data show that GHS-R1a is localized in the vicinity of hippocampal excitatory synapses, and that its activation increases delivery of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-type receptors (AMPARs) to synapses, producing functional modifications at excitatory synapses. Moreover, GHS-R1a activation enhances two different paradigms of long-term potentiation in the hippocampus, activates the phosphatidylinositol 3-kinase, and increases GluA1 AMPAR subunit and stargazin phosphorylation. We propose that GHS-R1a activation in the hippocampus enhances excitatory synaptic transmission and synaptic plasticity by regulating AMPAR trafficking. Our study provides insights into mechanisms that may mediate the cognition-enhancing effect of ghrelin, and suggests a possible link between the regulation of energy metabolism and learning.
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http://dx.doi.org/10.1073/pnas.1313798111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890894PMC
January 2014

MAP1B-dependent Rac activation is required for AMPA receptor endocytosis during long-term depression.

EMBO J 2013 Aug 23;32(16):2287-99. Epub 2013 Jul 23.

Department of Neurobiology, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid (UAM), Madrid, Spain.

The microtubule-associated protein 1B (MAP1B) plays critical roles in neurite growth and synapse maturation during brain development. This protein is well expressed in the adult brain. However, its function in mature neurons remains unknown. We have used a genetically modified mouse model and shRNA techniques to assess the role of MAP1B at established synapses, bypassing MAP1B functions during neuronal development. Under these conditions, we found that MAP1B deficiency alters synaptic plasticity by specifically impairing long-term depression (LTD) expression. Interestingly, this is due to a failure to trigger AMPA receptor endocytosis and spine shrinkage during LTD. These defects are accompanied by an impaired targeting of the Rac1 activator Tiam1 at synaptic compartments. Accordingly, LTD and AMPA receptor endocytosis are restored in MAP1B-deficient neurons by providing additional Rac1. Therefore, these results indicate that the MAP1B-Tiam1-Rac1 relay is essential for spine structural plasticity and removal of AMPA receptors from synapses during LTD. This work highlights the importance of MAPs as signalling hubs controlling the actin cytoskeleton and receptor trafficking during plasticity in mature neurons.
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http://dx.doi.org/10.1038/emboj.2013.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746201PMC
August 2013