Publications by authors named "Shira Knafo"

27 Publications

  • Page 1 of 1

Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer's Disease.

Pharm Res 2020 Sep 4;37(10):183. Epub 2020 Sep 4.

Biophysics Institute, CSIC-UPV/EHU, University of the Basque Country (UPV/EHU), 48940, Leioa, Spain.

Purpose: Amyloid β (Aβ) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aβ drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer's disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aβ-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability.

Methods: Lipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken.

Results: The mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp: 6.28 ± 1.85 × 10 cm s).

Conclusion: This increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery. Graphical Abstract.
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http://dx.doi.org/10.1007/s11095-020-02915-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473970PMC
September 2020

MERLIN: a novel BRET-based proximity biosensor for studying mitochondria-ER contact sites.

Life Sci Alliance 2020 01 9;3(1). Epub 2019 Dec 9.

Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany

The contacts between the ER and mitochondria play a key role in cellular functions such as the exchange of lipids and calcium between both organelles, as well as in apoptosis and autophagy signaling. The molecular architecture and spatiotemporal regulation of these distinct contact regions remain obscure and there is a need for new tools that enable tackling these questions. Here, we present a new bioluminescence resonance energy transfer-based biosensor for the quantitative analysis of distances between the ER and mitochondria that we call MERLIN (Mitochondria-ER Length Indicator Nanosensor). The main advantages of MERLIN compared with available alternatives are that it does not rely on the formation of artificial physical links between the two organelles, which could lead to artifacts, and that it allows to study contact site reversibility and dynamics. We show the applicability of MERLIN by characterizing the role of the mitochondrial dynamics machinery on the contacts of this organelle with the ER.
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http://dx.doi.org/10.26508/lsa.201900600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910062PMC
January 2020

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

Evidence of conditioned behavior in amoebae.

Nat Commun 2019 08 15;10(1):3690. Epub 2019 Aug 15.

Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, 48940, Spain.

Associative memory is the main type of learning by which complex organisms endowed with evolved nervous systems respond efficiently to certain environmental stimuli. It has been found in different multicellular species, from cephalopods to humans, but never in individual cells. Here we describe a motility pattern consistent with associative conditioned behavior in the microorganism Amoeba proteus. We use a controlled direct-current electric field as the conditioned stimulus, and a specific chemotactic peptide as the unconditioned stimulus. The amoebae are capable of linking two independent past events, generating persistent locomotion movements that can prevail for 44 min on average. We confirm a similar behavior in a related species, Metamoeba leningradensis. Thus, our results indicate that unicellular organisms can modify their behavior during migration by associative conditioning.
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http://dx.doi.org/10.1038/s41467-019-11677-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695432PMC
August 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

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

Editorial on the Special Issue: Molecules and Cognition.

Neuroscience 2018 02 4;370:1-3. Epub 2017 Nov 4.

Molecular Cognition Laboratory, Biophysics Institute, CSIC-UPV/EHU, Campus Universidad del País Vasco, Barrio Sarriena s/n, 48940 Leioa, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Basque Country, Spain; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. Electronic address:

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http://dx.doi.org/10.1016/j.neuroscience.2017.11.003DOI Listing
February 2018

Peptides Acting as Cognitive Enhancers.

Neuroscience 2018 02 10;370:81-87. Epub 2017 Oct 10.

Molecular Cognition Laboratory, Biophysics Institute, CSIC-UPV/EHU, Campus Universidad del País Vasco, Barrio Sarriena s/n, 48940 Leioa, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Basque Country, Spain; Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel. Electronic address:

The aim of this paper is to present an overview of three peptides that, by improving synaptic function, enhance learning and memory in laboratory rodents. We summarize their structure, their mechanisms of action, and their effects on synaptic and cognitive function. First we describe FGL, a peptide derived from the neural cell adhesion molecule which improves cognition by the activation of the PKC pathway that triggers an activity-dependent delivery of AMPA receptors to the synapses. Then we describe PTD4-PI3KAc peptide that by activating PI3K signaling pathway it promotes synapse and spine formation and enhances hippocampal dependent memory. Lastly, we describe a new peptide derived from the well-known tumor suppressor PTEN that prevents pathological interactions between PTEN and PDZ proteins at synapses during exposure to Amyloid beta. This action prevents memory deterioration in mouse model of Alzheimer's disease. Together, this review indicates how learning and memory can be improved by manipulating synaptic function and number through pharmacological treatment with peptides, and it establishes synaptic function as a valid target for cognitive enhancement.
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http://dx.doi.org/10.1016/j.neuroscience.2017.10.002DOI Listing
February 2018

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

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

Specific cytoarchitectureal changes in hippocampal subareas in daDREAM mice.

Mol Brain 2016 Feb 29;9:22. Epub 2016 Feb 29.

Spanish Network for Biomedical Research in Neurodegenerative Diseases, CIBERNED, Madrid, Spain.

Background: Transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a Ca(2+)-binding protein that regulates Ca(2+) homeostasis through gene regulation and protein-protein interactions. It has been shown that a dominant active form (daDREAM) is implicated in learning-related synaptic plasticity such as LTP and LTD in the hippocampus. Neuronal spines are reported to play important roles in plasticity and memory. However, the possible role of DREAM in spine plasticity has not been reported.

Results: Here we show that potentiating DREAM activity, by overexpressing daDREAM, reduced dendritic basal arborization and spine density in CA1 pyramidal neurons and increased spine density in dendrites in dentate gyrus granule cells. These microanatomical changes are accompanied by significant modifications in the expression of specific genes encoding the cytoskeletal proteins Arc, Formin 1 and Gelsolin in daDREAM hippocampus.

Conclusions: Our results strongly suggest that DREAM plays an important role in structural plasticity in the hippocampus.
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http://dx.doi.org/10.1186/s13041-016-0204-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772309PMC
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

DREAM controls the on/off switch of specific activity-dependent transcription pathways.

Mol Cell Biol 2014 Mar 23;34(5):877-87. Epub 2013 Dec 23.

National Center of Biotechnology, CSIC and CIBERNED, Madrid, Spain.

Changes in nuclear Ca(2+) homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K(+) channel interacting protein 3), is a Ca(2+)-binding protein that binds DNA and represses transcription in a Ca(2+)-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca(2+)-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory.
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http://dx.doi.org/10.1128/MCB.00360-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023831PMC
March 2014

Microscale AMPAR reorganization and dynamics of the postsynaptic density.

J Neurosci 2012 May;32(21):7103-5

Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California 94304, USA.

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http://dx.doi.org/10.1523/JNEUROSCI.1048-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622299PMC
May 2012

Common pathways for growth and for plasticity.

Curr Opin Neurobiol 2012 Jun 5;22(3):405-11. Epub 2012 Mar 5.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Madrid 28049, Spain.

Cell growth and differentiation in developing tissues are, at first impression, quite different endeavors from readjusting synaptic strength during activity-dependent synaptic plasticity in mature neurons. Nevertheless, it is becoming increasingly clear that these two distinct processes share multiple intracellular signaling events. How these common pathways result in cell division (during proliferation), large-scale cellular remodeling (during differentiation) or synapse-specific changes (during synaptic plasticity) is only starting to be elucidated. Here we review the latest findings on two prototypical examples of these shared mechanisms: the Ras-PI3K pathway and the intracellular signaling elicited by neural cell adhesion molecules interacting with growth factor receptors.
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http://dx.doi.org/10.1016/j.conb.2012.02.008DOI Listing
June 2012

Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement.

PLoS Biol 2012 Feb 21;10(2):e1001262. Epub 2012 Feb 21.

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

Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer.
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http://dx.doi.org/10.1371/journal.pbio.1001262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283560PMC
February 2012

Spines, plasticity, and cognition in Alzheimer's model mice.

Neural Plast 2012 28;2012:319836. Epub 2011 Nov 28.

Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

The pathological hallmarks of Alzheimer's disease (AD)--widespread synaptic and neuronal loss and the pathological accumulation of amyloid-beta peptide (Aβ) in senile plaques, as well as hyperphosphorylated tau in neurofibrillary tangles--have been known for many decades, but the links between AD pathology and dementia and effective therapeutic strategies remain elusive. Transgenic mice have been developed based on rare familial forms of AD and frontotemporal dementia, allowing investigators to test in detail the structural, functional, and behavioral consequences of AD-associated pathology. Here, we review work on transgenic AD models that investigate the degeneration of dendritic spine structure, synaptic function, and cognition. Together, these data support a model of AD pathogenesis in which soluble Aβ initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. These changes in synapse structure and function as well as frank synapse and neuronal loss contribute to the neural system dysfunction which causes cognitive deficits. Understanding the underpinnings of dementia in AD will be essential to develop and evaluate therapeutic approaches for this widespread and devastating disease.
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http://dx.doi.org/10.1155/2012/319836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238410PMC
April 2012

PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression.

EMBO J 2010 Aug 13;29(16):2827-40. Epub 2010 Jul 13.

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is an important regulator of phosphatidylinositol-(3,4,5,)-trisphosphate signalling, which controls cell growth and differentiation. However, PTEN is also highly expressed in the adult brain, in which it can be found in dendritic spines in hippocampus and other brain regions. Here, we have investigated specific functions of PTEN in the regulation of synaptic function in excitatory hippocampal synapses. We found that NMDA receptor activation triggers a PDZ-dependent association between PTEN and the synaptic scaffolding molecule PSD-95. This association is accompanied by PTEN localization at the postsynaptic density and anchoring within the spine. On the other hand, enhancement of PTEN lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses. This activity is specifically required for NMDA receptor-dependent long-term depression (LTD), but not for LTP or metabotropic glutamate receptor-dependent LTD. Therefore, these results reveal PTEN as a regulated signalling molecule at the synapse, which is recruited to the postsynaptic membrane upon NMDA receptor activation, and is required for the modulation of synaptic activity during plasticity.
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http://dx.doi.org/10.1038/emboj.2010.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924645PMC
August 2010

PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane.

Nat Neurosci 2010 Jan 13;13(1):36-44. Epub 2009 Dec 13.

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Despite their low abundance, phosphoinositides are critical regulators of intracellular signaling and membrane compartmentalization. However, little is known of phosphoinositide function at the postsynaptic membrane. Here we show that continuous synthesis and availability of phosphatidylinositol-(3,4,5)-trisphosphate (PIP(3)) at the postsynaptic terminal is necessary for sustaining synaptic function in rat hippocampal neurons. This requirement was specific for synaptic, but not extrasynaptic, AMPA receptors, nor for NMDA receptors. PIP(3) downregulation impaired PSD-95 accumulation in spines. Concomitantly, AMPA receptors became more mobile and migrated from the postsynaptic density toward the perisynaptic membrane within the spine, leading to synaptic depression. Notably, these effects were only revealed after prolonged inhibition of PIP(3) synthesis or by direct quenching of this phosphoinositide at the postsynaptic cell. Therefore, we conclude that a slow, but constant, turnover of PIP(3) at synapses is required for maintaining AMPA receptor clustering and synaptic strength under basal conditions.
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http://dx.doi.org/10.1038/nn.2462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810846PMC
January 2010

Morphological alterations to neurons of the amygdala and impaired fear conditioning in a transgenic mouse model of Alzheimer's disease.

J Pathol 2009 Sep;219(1):41-51

Instituto Cajal (CSIC), Madrid, Spain.

Patients with Alzheimer's disease (AD) suffer from impaired memory and emotional disturbances, the pathogenesis of which is not entirely clear. In APP/PS1 transgenic mice, a model of AD in which amyloid beta (Abeta) accumulates in the brain, we have examined neurons in the lateral nucleus of the amygdala (LA), a brain region crucial to establish cued fear conditioning. We found that although there was no neuronal loss in this region and Abeta plaques only occupy less than 1% of its volume, these mice froze for shorter times after auditory fear conditioning when compared to their non-transgenic littermates. We performed a three-dimensional analysis of projection neurons and of thousands of dendritic spines in the LA. We found changes in dendritic tree morphology and a substantial decrease in the frequency of large spines in plaque-free neurons of APP/PS1 mice. We suggest that these morphological changes in the neurons of the LA may contribute to the impaired auditory fear conditioning seen in this AD model.
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http://dx.doi.org/10.1002/path.2565DOI Listing
September 2009

Olfactory learning-induced morphological modifications in single dendritic spines of young rats.

Eur J Neurosci 2005 Apr;21(8):2217-26

Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University, Beersheva, Israel.

Learning-related morphological modifications in single dendritic spines were studied quantitatively in the brains of young Sprague-Dawley rats. We have previously shown that olfactory discrimination rule-learning results in transient physiological and morphological modifications in piriform cortex pyramidal neurons. In particular, spine density along the apical dendrites of neurons from trained rats is increased after learning. The aim of the present study was to identify and describe olfactory learning-induced modifications in the morphology of single spines along apical dendrites of the same type of neurons. By using laser-scanning confocal microscopy, we show that 3 days after training completion spines on neurons from olfactory discrimination trained rats are shorter as compared to spines on neurons from control rats. Further analysis revealed that spine shortening attributed to olfactory discrimination learning derives from shortening of spine head and not from shortening of spine neck. In addition, detailed analysis of spine head volume suggests that spines with large heads are absent after learning. As spine head size may be related to the efficacy of the synapse it bears, we suggest that modifications in spine head dimensions following olfactory rule-learning enhance the cortical network ability to enter into a 'learning mode', in which memories of new odours can be acquired rapidly and efficiently.
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http://dx.doi.org/10.1111/j.1460-9568.2005.04041.xDOI Listing
April 2005

Dynamics of learning-induced spine redistribution along dendrites of pyramidal neurons in rats.

Eur J Neurosci 2005 Feb;21(4):927-35

Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University, Geersheva, Israel.

We have previously shown that olfactory-discrimination (OD) learning is accompanied by enhanced spine density along proximal apical dendrites of layer II pyramidal neurons in the piriform (olfactory) cortex. Here we studied the temporal dynamics of learning-induced modifications in dendritic spine density throughout the dendritic trees of these neurons. We observed a transient increase in proximal apical spine density after OD learning, suggesting a strengthening of intrinsic excitatory inputs interconnecting neurons within the olfactory cortex. By contrast, the afferent pathway receiving direct input from the olfactory bulb shows spine pruning, suggesting that the connectivity is weakened. The changes in spine density can be attributed to a net change in number of spines, as the morphometric parameters of the dendrites are unaffected by learning. We suggest that spine density changes may represent a mechanism of selective synaptic reorganization required for olfactory learning consolidation.
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http://dx.doi.org/10.1111/j.1460-9568.2005.03936.xDOI Listing
February 2005

Dynamics of olfactory learning-induced up-regulation of L1 in the piriform cortex and hippocampus.

Eur J Neurosci 2005 Jan;21(2):581-6

Faculty of Health Sciences and Zlotowski Centre for Neuroscience, Ben-Gurion University, Beersheva, Israel.

L1 is a cell adhesion molecule implicated in the formation of neural circuits and synaptic plasticity. We have examined the sequence and time-frame in which modifications in the synaptic expression of L1 occur in the piriform cortex and hippocampus in the course of rule learning of an olfactory discrimination task. Rats were trained to choose the correct odour in a pair to be rewarded with drinking water. Such training requires 6-8 days on average before rats reach maximal performance. We observed a learning-induced L1 up-regulation that occurred at an early training stage in the piriform cortex but only after rule-learning establishment in the hippocampus. We suggest that the dynamics of L1 up-regulation may reflect the functional role of these brain regions in olfactory rule learning.
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http://dx.doi.org/10.1111/j.1460-9568.2005.03862.xDOI Listing
January 2005

Olfactory learning-related NCAM expression is state, time, and location specific and is correlated with individual learning capabilities.

Hippocampus 2005 ;15(3):316-25

Faculty of Health Sciences and Zlotowski Centre for Neuroscience, Ben-Gurion University, Beersheva, Israel.

The notion that long-term synaptic plasticity is generated by activity-induced molecular modifications is widely accepted. It is well established that neural cell adhesion molecule (NCAM) is one of the prominent modulators of synaptic plasticity. NCAM can be polysialylated (PSA-NCAM), a reaction that provides it with anti-adhesion properties. In this study we have focused on NCAM and on its polysialylated state, and their relation to learning of an olfactory discrimination task, which depends on both the piriform (olfactory) cortex and hippocampus. We trained rats to distinguish between pairs of odors until rule learning was achieved, a process that normally lasts 6-8 days. At four time points, during training and after training completion, synaptic NCAM and PSA-NCAM expression were assessed in the piriform cortex and hippocampus. We report that NCAM modulation is specific to PSA-NCAM, which is upregulated in the hippocampus one day after training completion. We also report a correlation between the performance of individual rats in an early training stage and their NCAM expression, both in the piriform cortex and hippocampus. Since individual early performance in our odor discrimination task is correlated with the performance throughout the training period, we conclude that early NCAM expression is associated with odor learning capability. We therefore suggest that early synaptic NCAM expression may be one of the factors determining the capability of rats to learn.
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http://dx.doi.org/10.1002/hipo.20052DOI Listing
July 2005

Olfactory learning-induced increase in spine density along the apical dendrites of CA1 hippocampal neurons.

Hippocampus 2004 ;14(7):819-25

Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University, Beersheva, Israel.

We have previously shown that rule learning of an olfactory discrimination task is accompanied by increased spine density along the apical dendrites of piriform cortex pyramidal neurons. The purpose of the present study was to examine whether such olfactory learning task, in which the hippocampus is actively involved, induces morphological modifications in CA1 pyramidal neurons as well. Rats were trained to discriminate positive cues in pairs of odors for a water reward. Morphological modifications were studied in Golgi-impregnated neurons with light microscopy, 1 and 3 days after training completion. Spine densities were measured on the proximal region of apical dendrites and on basal dendrites after rule learning. Three days after training completion, the mean spine density on apical dendrites in neurons from trained rats was significantly higher by 20.5% than in neurons from pseudo-trained and naive animals, which did not differ from each other. By contrast, there was no significant difference in spine density of basal dendrites among the three groups. As length and diameter of spiny dendritic segments did not change after learning, the learning-related increase in spine density in neurons from trained rats may reflect a net increase in the number of excitatory synapses in the hippocampus following olfactory rule learning.
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http://dx.doi.org/10.1002/hipo.10219DOI Listing
January 2005