Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice

Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice Drexel Romanov Wood Weger Heilbronn Wulff Tasan Harkany

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Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice 2017 The Journal of Neuroscience 10.1523/jneurosci.3456-16.2017 Drexel2017-selective-silencing-of-hippocampal-parvalbum Drexel2017-selective-silencing-of-hippocampal-parvalbum.txt, the project's staged copy 9e173fad0a4d5b2936187beb94b6edb9b87670c7 not-redistributable neuroscience

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them whether losing GABA release from parvalbumin interneurons in the ventral subiculum is by itself enough to produce temporal lobe epilepsy Quotation withheld because this record is not cleared for redistribution. whether a correlation seen in patients and models - selective loss of these cells - is causal, and whether the effect needs the silencing to be permanent Quotation withheld because this record is not cleared for redistribution. permanent silencing produces spontaneous recurrent seizures with no neurodegeneration, while transient silencing of the same cells produces nothing unless an excitatory challenge is added Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. temporal lobe epileptogenesis Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms sustained loss of perisomatic feedforward inhibition from parvalbumin basket cells lowers the seizure threshold of subicular pyramidal cells, which then generates spike-wave clusters and spontaneous seizures Quotation withheld because this record is not cleared for redistribution. mechanisms compensatory readaptation of the disturbed circuit (e.g. sprouting of inhibitory terminals) gradually damps the seizure rate after several weeks Quotation withheld because this record is not cleared for redistribution. tetanus toxin light chain cleaves synaptobrevin, so GABA release is permanently gone from the transduced cells while the cells themselves survive Quotation withheld because this record is not cleared for redistribution. and the resulting loss of perisomatic feedforward inhibition lowers the seizure threshold enough that a subconvulsive dose precipitates convulsions and then lasting epilepsy Quotation withheld because this record is not cleared for redistribution. these cells are described as crucial during excitatory challenge and transiently dispensable under basal conditions, which is why a short silencing does nothing on its own Quotation withheld because this record is not cleared for redistribution. with the later decline in seizure frequency attributed to unknown readaptation - inhibitory sprouting, reduced cannabinoid signaling, or compensation by untransduced cells Quotation withheld because this record is not cleared for redistribution. Vector expression was not confined to the subiculum, so silenced PV neurons elsewhere in the hippocampus may have contributed. what this limits: the attribution of the effect to subicular PV neurons: WE CANNOT EXCLUDE A CONTRIBUTION OF PV NEURONS SILENCED TO SOME EXTENT ALSO IN OTHER HIPPOCAMPAL SUBFIELDS Quotation withheld because this record is not cleared for redistribution. The absence of any change in overall evoked or miniature postsynaptic currents after silencing is unexplained. what this limits: the absence of change in evoked or miniature postsynaptic currents after silencing: THERE IS NO CLEAR EXPLANATION FOR THIS Quotation withheld because this record is not cleared for redistribution. Why seizure frequency declines after about five weeks is not known. what this limits: the decline in seizure frequency after about five weeks: THE UNDERLYING MECHANISMS ARE UNCLEAR Quotation withheld because this record is not cleared for redistribution. The seizure frequency the model produces is modest in absolute terms - roughly one to two per week - but still ABOVE the range most patients with temporal lobe epilepsy experience. what this limits: the model's relevance to patients: THE FREQUENCY OF SRSs IS MODEST (APPROXIMATELY ONE TO TWO PER WEEK) BUT STILL BEYOND THE RANGE OF SEIZURE FREQUENCY IN MOST TLE PATIENTS · note: claim corrected 2026-08-20 by the project. The previous text read 'The seizure frequency obtained is low relative to most patients with temporal lobe epilepsy.', which REVERSES its own quote: the paper says the rate is modest 'BUT STILL BEYOND the range of seizure frequency in most TLE…'. limitations[6], grounded on the same sentence, already read it correctly, and the disagreement between the two is what exposed it. The quote, the anchor and the scope are unchanged. Quotation withheld because this record is not cleared for redistribution. the vector reached about 61% of parvalbumin cells and spilled beyond the subiculum, so a contribution from other subfields cannot be excluded what this limits: the anatomical specificity of the manipulation: THE INJECTIONS WERE NOT EXCLUSIVELY RESTRICTED TO THE SUBICULUM, BUT OFTEN ALSO AFFECTED SOME PV-CONTAINING INTERNEURONS IN SECTOR CA1 AND THE PRESUBICULUM AND PARASUBICULUM Quotation withheld because this record is not cleared for redistribution. the standard synaptic measures showed nothing, and the paper says there is no clear explanation for that what this limits: the mechanistic account of the behavioural effect: DESPITE THE SIGNIFICANT EFFECTS OF VECTOR INJECTIONS ON THE BEHAVIOR OF THE ANIMALS, NEITHER OVERALL eIPSCs OR EVOKED EPSCs NOR mIPSCs OR mEPSCs WERE AFFECTED IN SUBICULAR PYRAMIDAL CELLS Quotation withheld because this record is not cleared for redistribution. the seizure frequency the model produces is above what most patients with this epilepsy experience duplicate of: limitations[3] · what this limits: the same scope as limitations[3] - the seizure rate is above the clinical range Quotation withheld because this record is not cleared for redistribution. the frequency of SRSs appeared to decline after several weeks, the underlying mechanisms are unclear, and one may consider a variety of mechanisms responsible for this what this limits: the time course of the effect: THE FREQUENCY OF SRSs APPEARED TO DECLINE AFTER SEVERAL WEEKS. THE UNDERLYING MECHANISMS ARE UNCLEAR Quotation withheld because this record is not cleared for redistribution. a Cre-dependent viral construct carrying tetanus toxin light chain, used to make a silencing permanent rather than reversible Quotation withheld because this record is not cleared for redistribution. the designer-receptor system, imported specifically to supply the SHORT time course the toxin cannot give Quotation withheld because this record is not cleared for redistribution. a CB1 agonist used not as a treatment but as a subtraction, to remove one inhibitory source so the other becomes visible Quotation withheld because this record is not cleared for redistribution. the observation that these cells are preferentially lost in patients, which is the correlation the whole experiment tries to convert into a cause Quotation withheld because this record is not cleared for redistribution. a matched GFP vector injected the same way, monitored for the same 6 to 8 weeks eliminates: the injection of a vector as the cause - none of the AAV-GFP-injected mice exhibited C-SWDs or SRSs during the 6-8 week recording period · outcome: held Quotation withheld because this record is not cleared for redistribution. the transient-silencing drug given together with a threshold dose of the convulsant, in a separate group eliminates: the reading that the transient manipulation simply failed to reduce GABA release - the null is a null about DURATION, not about whether anything happened · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. the same threshold-dose challenge given 10 days after injection, to mice with only a few discharges and no seizures eliminates: kindling by repeated discharges as the source of the lowered threshold, since the threshold is already down before the discharges accumulate · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. a cannabinoid agonist applied to suppress release from the OTHER basket cell population before measuring eliminates: the apparent absence of any synaptic effect - the manipulation is invisible until the competing inhibitory source is removed · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. double labeling of 2724 transduced neurons against GABA, parvalbumin and somatostatin in 25 mice eliminates: silencing of the wrong cell class as the explanation - though it also shows the classes overlap · outcome (stated by the tagger, no quotation): partial Quotation withheld because this record is not cleared for redistribution. an activity marker counted across the hippocampal formation and neighbouring cortices eliminates: the possibility that the recorded events were local EEG artefacts rather than propagating seizures · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. GABA GABA Quotation withheld because this record is not cleared for redistribution. transient transient Quotation withheld because this record is not cleared for redistribution. threshold threshold Quotation withheld because this record is not cleared for redistribution. CNO CNO Quotation withheld because this record is not cleared for redistribution. THE DURATION OF THE MANIPULATION IS THE VARIABLE, NOT ITS TARGET: permanent silencing of these cells produces recurrent seizures, and TRANSIENT inhibition OF THE SAME CELLS IN THE SAME PLACE lowers the threshold but induces neither acute nor recurrent seizures Quotation withheld because this record is not cleared for redistribution. stated again as the conclusion - ONLY SUSTAINED, BUT NOT TRANSIENT, inhibition of GABA release is capable of inducing seizures or epilepsy Quotation withheld because this record is not cleared for redistribution. AND THE NULL IS A NULL ONLY WITHOUT A PROBE: transient inhibition combined with a threshold dose of the convulsant produced discharges and acute seizures within two hours - these cells are CRUCIAL PROTECTORS DURING EXCITATORY CHALLENGE while TRANSIENTLY DISPENSABLE UNDER BASAL CONDITIONS Quotation withheld because this record is not cleared for redistribution. with the control that makes the null readable at all - a separate group shows the drug DID impair GABA release, so the absence of seizures is about duration and not about whether the manipulation worked Quotation withheld because this record is not cleared for redistribution. THE STANDARD MEASURES ARE BLIND TO THE MANIPULATION AND THE PAPER SAYS SO: neither evoked nor miniature currents were affected despite the behavioral effect - THERE IS NO CLEAR EXPLANATION FOR THIS Quotation withheld because this record is not cleared for redistribution. and the effect only appears once a competing source is pharmacologically removed - suppressing release from the OTHER basket cell population unmasks a reduction that the unsubtracted measure cannot see Quotation withheld because this record is not cleared for redistribution. measured as a difference of two subtractions - 33% reduction in controls against 59% in treated animals, where the raw amplitudes did not differ at all Quotation withheld because this record is not cleared for redistribution. A SELECTIVITY CLAIM WITH ITS OWN NUMBERS: 95.7% of transduced cells contained GABA, 83.2% parvalbumin and 23.7% somatostatin, from 2724 cells in 25 mice Quotation withheld because this record is not cleared for redistribution. AND THE CATEGORIES OVERLAP, SO THE SELECTIVE MANIPULATION IS NOT SELECTIVE TO ONE FUNCTION: 15 to 30% of parvalbumin neurons ALSO contain somatostatin, and those cells - a different circuit motif - WERE THEREFORE ALSO AFFECTED Quotation withheld because this record is not cleared for redistribution. with the anatomical leak declared too - the injections were not exclusively restricted to the target, and a contribution from other subfields CANNOT BE EXCLUDED Quotation withheld because this record is not cleared for redistribution. and the coverage stated as a fraction rather than as success - 61.4% of parvalbumin interneurons at the injection site Quotation withheld because this record is not cleared for redistribution. A LATENT STATE REVEALED BY A PROBE: mice with discharges but no seizures were already primed, and a threshold dose converted every one of them - and they then had recurrent seizures for the following two weeks Quotation withheld because this record is not cleared for redistribution. AND A RIVAL EXPLANATION ELIMINATED BY MOVING THE PROBE EARLIER IN TIME: challenging at 10 days, before discharges could accumulate, shows the lowered threshold is not kindling by repeated discharges Quotation withheld because this record is not cleared for redistribution. EPILEPSY WITHOUT CELL LOSS, WHICH IS WHAT MAKES IT A MODEL OF THE NONLESIONAL CASE: recurrent seizures develop NOTABLY WITHOUT SIGNS OF NEURODEGENERATION Quotation withheld because this record is not cleared for redistribution. THE EFFECT FADES AND NOBODY KNOWS WHY: the seizure frequency declines after several weeks, THE UNDERLYING MECHANISMS ARE UNCLEAR, and five candidate mechanisms are listed with none tested Quotation withheld because this record is not cleared for redistribution. and the model is declared out of range of the disease it models - the seizure frequency is BEYOND THE RANGE of most patients with this epilepsy Quotation withheld because this record is not cleared for redistribution. AN INHIBITORY CELL CLASS THAT MAY BE EXCITATORY: axo-axonic cells, silenced along with the rest, MAY ALSO EXERT AN EXCITATORY FUNCTION through a locally reversed chloride gradient Quotation withheld because this record is not cleared for redistribution. with the competing account of the same disease quoted in full - a deficit in DENDRITIC feedback inhibition lowers the threshold, while augmented SOMATIC feedforward inhibition limits epileptiform activity Quotation withheld because this record is not cleared for redistribution. claim_type: mechanism a second reading reaching the same value. Recorded: mechanism — note: a second reading reaching the same value from a different sentence. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: two silencing tools with different time courses applied to the same cells in the same place, so that duration is the manipulated variable a second reading DIFFERING from the recorded value. Recorded: electrophysiology — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. phenomenon: temporal lobe epilepsy developing over a silent phase after an initial insult, with the mechanism of the transition poorly understood a second reading DIFFERING from the recorded value. Recorded: temporal lobe epileptogenesis — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. builds-on → Andrioli et al. (2007), Knopp et al. (2008) and Drexel et al. (2011), reporting selective loss of subicular PV interneurons in TLE patients and animal models Quotation withheld because this record is not cleared for redistribution. extends → Cammarota et al. (2013), Lee et al. (2014) and Toyoda et al. (2015) on the protective role of fast-spiking PV basket cells at seizure onset Quotation withheld because this record is not cleared for redistribution. replicates → Murray et al. (2011) Quotation withheld because this record is not cleared for redistribution. supports → the causal role of parvalbumin interneuron loss in the subiculum in the development of temporal lobe epilepsy differs in: Quotation withheld Quotation withheld because this record is not cleared for redistribution. qualifies → the reading that silencing these interneurons causes seizures - it does so only if the silencing is sustained differs in: only irreversible silencing of PV neurons by TeLC expression, but not a transient inhibition Quotation withheld because this record is not cleared for redistribution. contradicts → the requirement that epilepsy in this model be accompanied by neurodegeneration Quotation withheld because this record is not cleared for redistribution. distinguishes-from → kindling by accumulated discharges as the source of the lowered seizure threshold differs in: THE AXIS IS WHICH CAUSE PRODUCED THE THRESHOLD DROP. 'Quotation withheld.' The manipulation and its own downstream consequence are confounded by design - the silencing produces the discharges, and the discharges could produce the threshold change - so the paper names the loop before testing it. Quotation withheld because this record is not cleared for redistribution. critiques → its own synaptic measurements, which showed no effect and are left without a clear explanation differs in: THE AXIS IS WHICH LEVEL THE EFFECT APPEARS AT. 'Despite the significant effects of vector injections on the behavior of the animals, neither overall eIPSCs or evoked EPSCs nor mIPSCs or mEPSCs were affected in subicular pyramidal cells ... This is rather surprising.' A behavioural effect with no matching synaptic effect, reported as unexplained - the paper declines to reconcile its own two levels and says so. Quotation withheld because this record is not cleared for redistribution. supports → the account in which both dendritic and perisomatic inhibition matter, rather than one alone Quotation withheld because this record is not cleared for redistribution. PV —causes→ GABA PV GABA strength of the relation: 1 · note: GABA release inhibited SELECTIVELY from PV neurons, permanently, by a viral tetanus toxin light chain Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the study inhibited GABA RELEASE FROM PV neurons; 'PV causes GABA' is loose. Quotation withheld because this record is not cleared for redistribution. permanent —contrasted-with→ transient permanent transient strength of the relation: 1 · note: THE DURATION IS THE VARIABLE, NOT THE TARGET - transient inhibition of the SAME cells in the SAME place lowered the threshold but induced NEITHER acute NOR recurrent seizures Quotation withheld because this record is not cleared for redistribution. transient —causes→ threshold transient threshold direction on the measure: reduces · strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span is cut before the threshold claim completes. Quotation withheld because this record is not cleared for redistribution. TeLC —contrasted-with→ DREADD TeLC DREADD differs in: THE AXIS IS PERMANENCE OF THE SILENCING, WITH THE TRANSIENT DURATION GIVEN. 'only irreversible silencing of PV neurons by TeLC expression, but not A TRANSIENT INHIBITION (FOR ~1 TO 2 H) through the DREADD system, results in C-SWDs or SRSs.' Both tools silence the same cells; the phenotype appears only for the irreversible one, so the result is about DURATION rather than about PV neurons - and a study using DREADDs would have found nothing and concluded differently. · strength of the relation: 1 · note: and the null turns positive with a probe - transient inhibition PLUS a threshold dose gave discharges and acute seizures, so these cells are CRUCIAL PROTECTORS DURING EXCITATORY CHALLENGE and TRANSIENTLY DISPENSABLE UNDER BASAL CONDITIONS Quotation withheld because this record is not cleared for redistribution. CNO —causes→ GABA CNO GABA direction on the measure: reduces · strength of the relation: 1 · note: THE CONTROL THAT MAKES THE NULL READABLE - a separate group shows the drug DID impair GABA release, so the absence of seizures is about duration, not about whether anything happened Quotation withheld because this record is not cleared for redistribution. PTZ —causes→ seizure PTZ seizure strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but PTZ is the convulsant challenge; the span shown is about verifying inhibition. Quotation withheld because this record is not cleared for redistribution. basket cell —causes→ eIPSC basket cell eIPSC strength of the relation: 1 · note: the effect appears only once a COMPETING SOURCE is pharmacologically removed - suppressing release from the OTHER basket cell population unmasks a reduction the unsubtracted measure cannot see Quotation withheld because this record is not cleared for redistribution. TeLC —causes→ eIPSC TeLC eIPSC strength of the relation: 1 · note: a difference of two subtractions - 33% reduction in controls against 59% in treated animals, where the raw amplitudes did not differ at all Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but TeLC-injected mice showed a larger WIN-induced eIPSC reduction (59% against 33%); causes is indirect and drops the comparison. Quotation withheld because this record is not cleared for redistribution. TeLC —causes→ EEG TeLC EEG strength of the relation: 1 · note: 88% showed clustered discharges by day 16 and 64% at least one spontaneous seizure by day 28; NONE of the control-vector mice showed either Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but AAV-TeLC injection produced spike-wave discharges and seizures SEEN IN the EEG; 'causes EEG' is loose. Quotation withheld because this record is not cleared for redistribution. neurodegeneration —distinct-from→ epilepsy neurodegeneration epilepsy strength of the relation: 1 · note: EPILEPSY WITHOUT CELL LOSS, which is what makes it a model of the nonlesional case - NOTABLY WITHOUT SIGNS OF NEURODEGENERATION Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but epilepsy was induced 'notably WITHOUT signs of neurodegeneration'; distinct-from is loose. Quotation withheld because this record is not cleared for redistribution. permanent —causes→ seizure permanent seizure strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says restricted inhibition induces recurrent discharges progressing to seizures; 'permanent' is a fragment endpoint. Quotation withheld because this record is not cleared for redistribution. threshold —operationalised-as→ PTZ threshold PTZ strength of the relation: 1 · note: A LATENT STATE REVEALED BY A PROBE - a threshold dose converted every primed mouse, and they then had recurrent seizures for the following two weeks Audit 2026-09-28: DOUBTFUL - read against its span and kept, but PTZ was used to test seizure threshold; operationalised-as is loose. Quotation withheld because this record is not cleared for redistribution. basket cell —causes→ pyramidal basket cell pyramidal strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says basket cells exert feedforward inhibition on pyramidal cells; causes 'pyramidal' drops 'inhibition'. Quotation withheld because this record is not cleared for redistribution. PV —part-of→ subiculum PV subiculum strength of the relation: 1 · note: the correlation the experiment tries to convert into a cause - PV interneurons preferentially lost in the subiculum of patients EVEN WITHOUT sclerosis Audit 2026-09-28: DOUBTFUL - read against its span and kept, but the span says PV interneurons are lost in the subiculum; part-of is loose. Quotation withheld because this record is not cleared for redistribution. pyramidal —part-of→ subiculum pyramidal subiculum strength of the relation: 1 Audit 2026-09-28: DOUBTFUL - read against its span and kept, but pyramidal neurons of the subiculum; part-of is loose. Quotation withheld because this record is not cleared for redistribution. Fisher's exact test Fisher's exact test Quotation withheld because this record is not cleared for redistribution. Kruskal-Wallis test Kruskal-Wallis test Quotation withheld because this record is not cleared for redistribution. ANOVA ANOVA Quotation withheld because this record is not cleared for redistribution. t-test t-test Quotation withheld because this record is not cleared for redistribution. statistical-significance statistical-significance Quotation withheld because this record is not cleared for redistribution. standard error of the mean standard error of the mean Quotation withheld because this record is not cleared for redistribution. Two-way repeated-measures ANOVA Two-way repeated-measures ANOVA Quotation withheld because this record is not cleared for redistribution. Kruskal–Wallis test Kruskal–Wallis test Quotation withheld because this record is not cleared for redistribution. eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs) and 64% showed spontaneous recurrent seizures (SRSs) Quotation withheld because this record is not cleared for redistribution. The epilepsy developed without any detectable loss of parvalbumin or GABA neurons, i.e. without neurodegeneration. Quotation withheld because this record is not cleared for redistribution. Transient chemogenetic silencing of PV neurons for 1-2 h induced no discharge clusters or seizures over the following 5 days. Quotation withheld because this record is not cleared for redistribution. Inhibiting GABA release from subicular/CA1 PV interneurons is by itself sufficient to lower the seizure threshold. Quotation withheld because this record is not cleared for redistribution. The manipulation selectively cut the parvalbumin-mediated component of inhibition onto subicular pyramidal cells while leaving cholecystokinin-basket-cell inhibition intact. Quotation withheld because this record is not cleared for redistribution. Seizure frequency did not grow indefinitely but fell back after about five weeks. Quotation withheld because this record is not cleared for redistribution. A PTZ dose provoked acute tonic-clonic seizures in all TeLC-injected mice but in only one of seven GFP controls and none of five wild-type mice. Quotation withheld because this record is not cleared for redistribution. THE DURATION OF THE MANIPULATION IS THE VARIABLE, NOT ITS TARGET: transient inhibition of the SAME cells in the SAME place lowered the seizure threshold but induced NEITHER acute NOR recurrent seizures Quotation withheld because this record is not cleared for redistribution. ONLY SUSTAINED, BUT NOT TRANSIENT, inhibition of GABA release from these neurons is capable of inducing seizures or epilepsy Quotation withheld because this record is not cleared for redistribution. AND THE NULL IS A NULL ONLY WITHOUT A PROBE: transient inhibition plus a threshold dose gave discharges and acute seizures - these cells are crucial protectors during excitatory challenge and TRANSIENTLY DISPENSABLE under basal conditions Quotation withheld because this record is not cleared for redistribution. with the control that makes the null readable - a separate group shows the drug DID impair GABA release Quotation withheld because this record is not cleared for redistribution. THE STANDARD MEASURES ARE BLIND TO THE MANIPULATION: neither evoked nor miniature currents were affected despite the behavioral effect, and THERE IS NO CLEAR EXPLANATION FOR THIS Quotation withheld because this record is not cleared for redistribution. and the effect appears only once a competing source is pharmacologically removed Quotation withheld because this record is not cleared for redistribution. measured as a difference of two subtractions - 33% reduction in controls against 59% in treated animals Quotation withheld because this record is not cleared for redistribution. A SELECTIVITY CLAIM WITH ITS OWN NUMBERS: 95.7% of transduced cells contained GABA, 83.2% parvalbumin and 23.7% somatostatin, from 2724 cells in 25 mice Quotation withheld because this record is not cleared for redistribution. AND THE CATEGORIES OVERLAP: 15 to 30% of parvalbumin neurons also contain somatostatin, and those cells WERE THEREFORE ALSO AFFECTED Quotation withheld because this record is not cleared for redistribution. with the anatomical leak declared - the injections were not exclusively restricted to the target and a contribution from other subfields CANNOT BE EXCLUDED Quotation withheld because this record is not cleared for redistribution. and the coverage stated as a fraction rather than as success - 61.4% of parvalbumin interneurons at the injection site Quotation withheld because this record is not cleared for redistribution. 22 of the 25 mice (88%) exhibited unprovoked C-SWDs, and NONE of the AAV-GFP-injected mice exhibited C-SWDs or SRSs during the 6-8 week recording period Quotation withheld because this record is not cleared for redistribution. EPILEPSY WITHOUT CELL LOSS: recurrent seizures develop NOTABLY WITHOUT SIGNS OF NEURODEGENERATION, which is what makes it a model of the nonlesional case Quotation withheld because this record is not cleared for redistribution. A LATENT STATE REVEALED BY A PROBE: mice with discharges but no seizures were already primed, and a threshold dose converted every one of them Quotation withheld because this record is not cleared for redistribution. AND A RIVAL ELIMINATED BY MOVING THE PROBE EARLIER IN TIME: challenging at 10 days shows the lowered threshold is not kindling by accumulated discharges Quotation withheld because this record is not cleared for redistribution. seizure frequency declined after several weeks, the mechanisms are unclear, and several candidate explanations are listed Quotation withheld because this record is not cleared for redistribution. and the model is declared out of range of the disease it models - the seizure frequency is BEYOND THE RANGE of most patients Quotation withheld because this record is not cleared for redistribution. axo-axonic cells may also exert an excitatory function through a locally reversed chloride gradient at their synapses Quotation withheld because this record is not cleared for redistribution. with the competing account quoted in full - a deficit in DENDRITIC feedback inhibition lowers the threshold while augmented SOMATIC feedforward inhibition limits epileptiform activity WHOSE RESULT THIS IS: Cossart et al. (2001) proposed - THE EVIDENCE FOR THIS ROW ATTRIBUTES THE WORK TO SOMEBODY ELSE. The cited name is the subject of a result verb and the sentence carries no first-person marker, so the finding, quantity or definition is the CITED author's rather than this record's. The claim is true and the quote is verbatim - what is wrong is whose result the corpus says it is. Nothing edited, nothing withdrawn: the row is marked so a page can name the source. Where the record is a commentary or review, its claim relations layer usually already names the paper being discussed - the record knows at one layer and forgets at another. Quotation withheld because this record is not cleared for redistribution. the transition from a normal to an epileptic brain takes years, and its cellular and molecular mechanisms are STILL POORLY UNDERSTOOD Quotation withheld because this record is not cleared for redistribution. ΔFosB was only barely expressed in controls and in mice that exhibited only C-SWDs, and prominently labeled neurons in the hippocampus, subiculum, and entorhinal and perirhinal cortices after frequent SRSs Quotation withheld because this record is not cleared for redistribution. with the human parallel stated - AS IN PATIENTS WITH NONLESIONAL TLE, these mice developed epilepsy without signs of neurodegeneration Quotation withheld because this record is not cleared for redistribution. and activating EITHER dendritic or perisomatic inhibition suppressed epileptiform activity, with all GABA neurons together more effective than either Quotation withheld because this record is not cleared for redistribution. seizure seizure Quotation withheld because this record is not cleared for redistribution. C-SWDs C-SWDs Quotation withheld because this record is not cleared for redistribution. DREADD (designer receptors exclusively activated by designer drugs) DREADD (designer receptors exclusively activated by designer drugs) Quotation withheld because this record is not cleared for redistribution. tetanus toxin light chain tetanus toxin light chain Quotation withheld because this record is not cleared for redistribution. TeLC TeLC Quotation withheld because this record is not cleared for redistribution. DREADD DREADD Quotation withheld because this record is not cleared for redistribution. feedforward feedforward Quotation withheld because this record is not cleared for redistribution. threshold threshold Quotation withheld because this record is not cleared for redistribution. seizure threshold seizure threshold Quotation withheld because this record is not cleared for redistribution. GFP vector GFP vector Quotation withheld because this record is not cleared for redistribution. threshold threshold Quotation withheld because this record is not cleared for redistribution. frequency frequency Quotation withheld because this record is not cleared for redistribution. expression expression Quotation withheld because this record is not cleared for redistribution. transient transient Quotation withheld because this record is not cleared for redistribution. 88% — proportion of vector-injected mice showing unprovoked clusters of spike-wave discharges by day 16 Quotation withheld because this record is not cleared for redistribution. 64% — proportion of TeLC-injected mice that went on to develop spontaneous recurrent seizures Quotation withheld because this record is not cleared for redistribution. 61.4 ± 2.43% — fraction of parvalbumin interneurons at the injection site that expressed the silencing construct Quotation withheld because this record is not cleared for redistribution. 89.5% — share of spontaneous seizures that were immediately preceded by a preictal discharge cluster Quotation withheld because this record is not cleared for redistribution. 24.6 ± 0.62 s — average duration of a spontaneous recurrent seizure Quotation withheld because this record is not cleared for redistribution. 40.0 ± 9.07 per month/mouse — rate of discharge clusters per mouse per month Quotation withheld because this record is not cleared for redistribution. F (1,20) = 4.72, p = 0.0419 — group effect on the cannabinoid-insensitive (parvalbumin-mediated) component of the evoked IPSC Quotation withheld because this record is not cleared for redistribution. 33% / 59% — reduction of evoked IPSC amplitude by the CB1 agonist in control versus silenced mice Quotation withheld because this record is not cleared for redistribution. ∼73% — share of mice in which discharge clusters progressed to spontaneous recurrent seizures Quotation withheld because this record is not cleared for redistribution. p = 0.0047 — significance of the difference in acute pentylenetetrazole-induced convulsions between silenced mice and controls Quotation withheld because this record is not cleared for redistribution. 61.4 ± 2.43% — of the target cells actually reached by the vector - the manipulation's coverage stated as a fraction, so 'selective silencing' in the title means silencing three cells in five Quotation withheld because this record is not cleared for redistribution. 95.7 ± 0.68%, 83.2 ± 1.27%, and 23.7 ± 1.61% — of transduced cells containing GABA, parvalbumin and somatostatin - the third number is the one that shows the target category is not one functional class Quotation withheld because this record is not cleared for redistribution. 15–30% — of parvalbumin neurons that also contain somatostatin, so a manipulation aimed at one circuit motif necessarily hits another Quotation withheld because this record is not cleared for redistribution. 33% ... 59% — the reduction in the amplitude of eIPSCs by WIN 55,212-2 in AAV-GFP-injected mice and in mice injected with AAV-TeLC Quotation withheld because this record is not cleared for redistribution. one to two per week — the seizure frequency the model produces, stated as being ABOVE what most patients experience - a model's severity reported against its target rather than on its own Quotation withheld because this record is not cleared for redistribution.

The full text of this article is not redistributable, so it is not included here. The evidence sentences are withheld with it; the tag layer and its grounding status remain. The article itself is at https://doi.org/10.1523/jneurosci.3456-16.2017.