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      NPTX2 and cognitive dysfunction in Alzheimer’s Disease

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          Abstract

          Memory loss in Alzheimer’s disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2 -/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.

          DOI: http://dx.doi.org/10.7554/eLife.23798.001

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          Index for rating diagnostic tests.

          W J YOUDEN, Michele Teng, Nancy Chabot … (1950)
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            Mechanisms of gamma oscillations.

            György Buzsáki, Xiao-Jing Wang (2012)
            Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the "operational modes" of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.
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              Dynamic predictions: oscillations and synchrony in top-down processing.

              A K Engel, P Fries, W. Singer (2001)
              Classical theories of sensory processing view the brain as a passive, stimulus-driven device. By contrast, more recent approaches emphasize the constructive nature of perception, viewing it as an active and highly selective process. Indeed, there is ample evidence that the processing of stimuli is controlled by top-down influences that strongly shape the intrinsic dynamics of thalamocortical networks and constantly create predictions about forthcoming sensory events. We discuss recent experiments indicating that such predictions might be embodied in the temporal structure of both stimulus-evoked and ongoing activity, and that synchronous oscillations are particularly important in this process. Coherence among subthreshold membrane potential fluctuations could be exploited to express selective functional relationships during states of expectancy or attention, and these dynamic patterns could allow the grouping and selection of distributed neuronal responses for further processing.
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                Author and article information

                Contributors
                Moses V Chao: Role: Reviewing editor
                Journal
                Journal ID (nlm-ta): eLife
                Journal ID (iso-abbrev): Elife
                Journal ID (hwp): eLife
                Journal ID (publisher-id): eLife
                Title: eLife
                Publisher: eLife Sciences Publications, Ltd
                ISSN (Electronic): 2050-084X
                Publication date (Electronic, pub): 23 March 2017
                Publication date Collection: 2017
                Volume: 6
                Electronic Location Identifier: e23798
                Affiliations
                [1 ]deptSolomon H. Snyder Department of Neuroscience , Johns Hopkins University School of Medicine , Baltimore, United States
                [2 ]deptDepartment of Physiology , Johns Hopkins University School of Medicine , Baltimore, United States
                [3 ]deptInstitute for Genetic Medicine , Johns Hopkins University School of Medicine , Baltimore, United States
                [4 ]deptProgram in Developmental Neurobiology , Eunice Kennedy-Shriver National Institute of Child Health and Human Development , Bethesda, United States
                [5 ]deptLaboratory of Behavioral Neuroscience , National Institute on Aging, Intramural Research Program , Baltimore, United States
                [6 ]deptDepartment of Pathology , Johns Hopkins University School of Medicine , Baltimore, United States
                [7 ]deptDepartment of Neurosciences , University of California San Diego Medical Center , San Diego, United States
                [8 ]deptShiley-Marcos Alzheimer's Disease Research Center , University of California San Diego Medical Center , San Diego, United States
                [9 ]deptDivision of Biostatistics and Bioinformatics , University of California San Diego , San Diego, United States
                [10 ]Institute for Basic Research , New York City, United States
                [11 ]deptTaub Institute for Research on Alzheimer’s disease and the Aging Brain , Columbia University , New York City, United States
                [12 ]deptDepartment of Neurology , Johns Hopkins University School of Medicine , Baltimore, United States
                New York University Langone Medical Center , United States
                New York University Langone Medical Center , United States
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-8481-6709
                http://orcid.org/0000-0002-1153-7335
                http://orcid.org/0000-0002-5086-614X
                Article
                Publisher ID: 23798
                DOI: 10.7554/eLife.23798
                PMC ID: 5404919
                PubMed ID: 28440221
                SO-VID: 7206e1fc-da7a-4889-8b5b-5c68e57c6aab
                Copyright © © 2017, Xiao et al
                License:

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                Date received : 01 December 2016
                Date accepted : 15 March 2017
                Related
                Funding
                Funded by: LuMind Research Down Syndrome Foundation;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;
                Award ID: AG05131
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: P50 AG005146-27
                Award Recipient :
                Funded by: Alzheimer’s drug discovery foundation;
                Award ID: 20021106
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: MH100024
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: R35 NS-097966
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Subject: Research Article
                Subject: Neuroscience
                Custom metadata
                elife-xml-version 2.5
                Author impact statement Dysfunction of pyramidal neuron-PV interneuron circuits contributes to cognitive failure in Alzheimer's disease.

                ScienceOpen disciplines: Life sciences
                Keywords: immediate early gene,inhibitory neuron,dementia,alzheimer's disease,mmediate early gene,alzheimer’s disease
                Data availability:
                ScienceOpen disciplines: Life sciences
                Keywords: immediate early gene, inhibitory neuron, dementia, alzheimer's disease, mmediate early gene, alzheimer’s disease

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