Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

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usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="B8Kgt9081qz9XWdhatPEXdfAwrFHgjtyrRlPe9CTIqbNtQyW5RD3zm4vkIwSgn8U"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="B8Kgt9081qz9XWdhatPEXdfAwrFHgjtyrRlPe9CTIqbNtQyW5RD3zm4vkIwSgn8U"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="B8Kgt9081qz9XWdhatPEXdfAwrFHgjtyrRlPe9CTIqbNtQyW5RD3zm4vkIwSgn8U"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="B8Kgt9081qz9XWdhatPEXdfAwrFHgjtyrRlPe9CTIqbNtQyW5RD3zm4vkIwSgn8U"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="23595016"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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Pennsylvania 19104-4399, USA." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Coulter+DA&cauthor_id=23595016" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Douglas A Coulter">Douglas A Coulter</a></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliation </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> The Children's Hospital of Philadelphia, Division of Neurology, Colket Translational Research Building, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4399, USA.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">23595016</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC3982383&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC3982383/" data-ga-category="full_text" data-ga-action="PMCID" > PMC3982383 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1038/nrn3482&id_type=DOI" href="https://doi.org/10.1038/nrn3482" data-ga-category="full_text" data-ga-action="DOI" > 10.1038/nrn3482 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button 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</span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause. The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis. Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge. Recent work has yielded important conceptual advances in this field. We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction. </p> </div> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" data-ga-category="literature_resources" data-ga-action="disclaimer_link" data-ga-label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one"><bold>Competing interests statement</bold></p> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare no competing financial interests.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/fa02d42d5455/nihms565825f1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="631" data-image-height="535" data-image-alt="Figure 1" data-pmc-id="PMC3982383" data-figure-id="F1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/470283f582b5/nihms565825f1.gif" alt="Figure 1" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="631"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="535"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1. Mechanistic roles of the mTOR… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1. Mechanistic roles of the mTOR pathway and REST in epileptogenesis </p> </strong> <div class="figure-caption-contents"><b> a </b> | A…</div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1. Mechanistic roles of the mTOR pathway and REST in epileptogenesis </strong> <div class="figure-caption-contents"><b>a</b> | A simplified version of the mammalian target of rapamycin (mTOR) pathway, highlighting epilepsy-related molecules. For a more complete illustration of the mTOR pathway, see REF. . <b>b</b> | A schematic depicting repressor element 1 (RE1)-silencing transcription factor (REST)-mediated gene silencing triggered by status epilepticus. REST co-repressor 1 (CoREST), a component of the histone deacetylase (HDAC) complex, interacts with REST to mediate transcriptional repression. The asterisk indicates genes for which there is specific experimental evidence suggesting regulation by REST or HDAC inhibiton after status epilepticus<sup>,</sup>. AMPK, AMP-activated protein kinase; <i>BDNF</i>, brain-derived neurotrophic factor; <i>GABRB3</i>; type A GABA receptor β3 subunit; <i>GABRD</i>; type A GABA receptor δ-subunit; <i>GRIA2</i>, ionotropic AMPA 2 glutamate receptor; <i>HCN1</i>, hyperpolarization-activated cyclic nucleotide-gated channel subunit 1; IRS1, insulin receptor substrate 1; <i>KCC2</i>; potassium/chloride co-transporter 2; <i>KCNC</i>, potassium voltage-gated channel subfamily C; LKB1, liver kinase B1 (also known as serine/threonine kinase STK11); mTORC1, mTOR complex 1; PDK1, 3-phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PtdIns(4,5)P<sub>2</sub>, phosphatidylinositol-4,5-biphosphate; PtdIns(3,4,5)P<sub>3</sub>, phosphatidylinositol-3,4,5-triphosphate; PTEN, phosphatase and tensin homologue; RHEB, RAS homologue enriched in brain; STRADA, STE20-related adaptor protein-α; TSC, tuberous sclerosis complex. Part <b>a</b> is modified, with permission, from REF. © (2011) Elsevier.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/e21f54ce6081/nihms565825f2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="800" data-image-height="365" data-image-alt="Figure 2" data-pmc-id="PMC3982383" data-figure-id="F2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/4f37cce08916/nihms565825f2.gif" alt="Figure 2" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="365"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2. Embedded loop structures of the… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2. Embedded loop structures of the temporal lobe </p> </strong> <div class="figure-caption-contents"><b> a </b> | The hippocampus receives two…</div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2. Embedded loop structures of the temporal lobe </strong> <div class="figure-caption-contents"><b>a</b> | The hippocampus receives two inputs, the perforant path (PP) and the temporoammonic (TA) pathway. The entorhinal cortex (EC) is in turn the target of hippocampal output, creating multiple excitatory loops. There is a long loop that originates from the EC and projects to the dentate gyrus (DG) via the PP, from the DG to area CA3 via mossy fibres (MFs), from area CA3 to area CA1 and from area CA1 back to the subiculum (not shown) and/or EC. An intermediate-length loop originates from the EC and projects to area CA3 (via the PP pathway), then to area CA1 and from there to the subiculum and/or EC. A short loop projects from the EC to area CA1 (via the TA pathway) and back to the subiculum and/or EC. Recurrent collaterals (RCs) between CA3 pyramidal cells (PCs) are also shown. <b>b</b> | Simplified connectivity within the DG. Many connections and various inhibitory interneuron subtypes are omitted for clarity<sup>,,</sup>. PCs and stellate cells within layer 2 of the medial EC (MEC) and lateral EC (LEC) form the PP to the middle and outer molecular layer, respectively, of the hippocampal DG, as well as to the distal dendrites of PCs in area CA3 (not shown). In the dentate, lateral PP (LPP) and medial PP (MPP) axons synapse onto dentate granule cells (GCs) and onto GABAergic interneurons (including parvalbumin-positive (PV<sup>+</sup>) basket cells and somatostatin-positive (SOM<sup>+</sup>) hilar PP-associated (HiPP) cells) as well as mossy cells in the dentate hilus. <b>c</b> | Selected connections of the TA pathway, which proceeds from layer 3 EC pyramidal and spiny stellate neurons (not shown) to the distal dendrites and distal apical tuft dendrites of CA1 neurons in stratum lacunosum-moleculare (SLM) in the short loop mentioned above as well as to the distal dendrites of CA2 (the intermediate-length loop, not shown). Extrinsic excitatory connections are shown in green; excitatory cells and intrinsic excitatory connections are shown in blue; and inhibitory cells and intrinsic inhibitory connections are shown in red and purple. Bi, bistratified cell; O-LM, oriens lacunosum-moleculare. SC, Schaffer collateral; SO, stratum oriens; SR, stratum radiatum.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/7c4757c58e6a/nihms565825f3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="800" data-image-height="443" data-image-alt="Figure 3" data-pmc-id="PMC3982383" data-figure-id="F3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/e06e01e66a5c/nihms565825f3.gif" alt="Figure 3" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="800"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="443"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3. Temporal lobe circuit elements under… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3. Temporal lobe circuit elements under normal conditions </p> </strong> <div class="figure-caption-contents"><b> A </b> | Dentate gating in the…</div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3. Temporal lobe circuit elements under normal conditions </strong> <div class="figure-caption-contents"><b>A</b> | Dentate gating in the hippocampus under normal conditions (parts <b>Aa</b>–<b>Ac</b>) and after blockade of GABAergic inhibition (parts <b>Ad</b>–<b>Af</b>). <b>Aa</b> | A voltage-sensitive dye (VSD) image of depolarization that is restricted to the dentate gyrus granule cell layer in response to stimulation of the perforant path in an acute brain slice from the rat hippocampus. <b>Ab</b> | The VSD response is quantified in the dentate gyrus, hilus and area CA3. <b>Ac</b> | The top panel shows a current-clamp recording from a dentate gyrus granule cell and the botttom panel shows the field potential in the dentate gyrus. <b>Ad</b> | The collapse of the dentate after blockade of GABAergic inhibition using 5 μM picrotoxin (PTX; a non-competitive type A (GABA<sub>A</sub>) receptor antagonist) is illustrated using VSD imaging. <b>Ae</b> | The quantification of the VSD response shows collapse of the dentate gate, with activation of upstream area CA3 after GABAergic blockade. <b>Af</b> | Blockade of inhibition elicits hyperactivation of dentate granule cells in response to perforant path activation, as shown by the current-clamp recording (top panel) and the field potential (bottom panel). <b>B</b> | Temporoammonic (TA) pathway function in area CA1 under normal conditions (parts <b>Ba</b>, <b>Bb</b>) and following GABAergic blockade (parts <b>Bc</b>, <b>Bd</b>). <b>Ba</b> | Activation within area CA1 in response to stimulation of the TA pathway is spatially restricted to the distal dendrites of CA1 pyramidal cells (indicated by the arrows), which is shown using VSD imaging. <b>Bb</b> | The top panel shows a current-clamp recording from a CA1 pyramidal cell dendrite in response to TA pathway activation, and the bottom panel shows the quantification of the VSD response in stratum oriens (SO), stratum radiatum (SR) and stratum lacunosum-moleculare (SLM) 30 ms after extracellular stimulation of the TA pathway, with evoked excitatory responses (indicated by the asterisk) in SLM. <b>Bc</b> | A VSD image shows that GABAergic feedforward inhibition after application of the GABA<sub>A</sub> antagonist gabazine (1 μm) and the GABA<sub>B</sub> antagonist CGP 55845A (2 μm) spatially restricts TA pathway activation to the distal dendrites of CA1 pyramidal cells, with loss of spatial segregation within area CA1. <b>Bd</b> | The top panel shows a current-clamp recording from a CA1 pyramidal cell dendrite, and the the bottom panel shows the quantification of the VSD response, with propagation of the response to SR and SO. <i>F</i>, fluorescence; nACSF, normal artificial cerebrospinal fluid. Part <b>A</b> is reproduced, with permission, from REF. © (2007) Elsevier. Part <b>B</b> is reproduced, with permission, from REF. © (2005) Society for Neuroscience.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/b6dde1ca9d2f/nihms565825f4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="593" data-image-height="939" data-image-alt="Figure 4" data-pmc-id="PMC3982383" data-figure-id="F4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5962/3982383/05b71b37d4ae/nihms565825f4.gif" alt="Figure 4" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="593"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="939"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4. Circuit dysfunction in temporal lobe… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4. Circuit dysfunction in temporal lobe epilepsy </p> </strong> <div class="figure-caption-contents"><b> a </b> | Dentate gating is impaired during…</div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4. Circuit dysfunction in temporal lobe epilepsy </strong> <div class="figure-caption-contents"><b>a</b> | Dentate gating is impaired during the latent period (1 week after status epilepticus) in an animal model of chronic temporal lobe epilepsy (TLE). The top panel shows voltage-sensitive dye (VSD) recordings of perforant path stimulation under control conditions 5 ms after stimulation (left), at peak (middle) and later (200 ms; right). The top right panel shows restriction of the perforant path-evoked depolarization to the molecular layer of the dentate gyrus (DG). Note that there is minimal area CA3 activation. During the latent period (bottom panel), identical stimulation reveals a delayed peak response as well as >200% increase in activation (as measured by areal pixel activation) in area CA3. <b>b</b> | Gating function is retained in the chronic phase of acquired TLE in the rodent model. The two panels show VSD images of the DG 5 ms (left), 25 ms (middle) and 200 ms (right) after stimulation of the perforant path in control rats (top panel) and in chronically epileptic rats (bottom panel). Under both conditions, there is a strong response in the DG that fails to propagate to area CA3. <b>c</b> | Temporoammonic (TA) pathway dysfunction in the chronic phase of acquired TLE. VSD imaging of TA pathway function in control animals (top panel) and epileptic animals (bottom panel) at 5 ms, 25 ms, 55 ms, 85 ms and 180 ms after stimulation of the TA pathway, producing spatially restricted activity in control animals that aberrantly propagates to the strata radiatum and pyramidale in the epileptic condition. Hil, hilus; <i>F</i>, fluorescence. Part <b>a</b> is reproduced, with permission, from REF. © (2007) Society for Neuroscience. 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Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction - PubMed