Temporal Lobe Epilepsy Research Articles

A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor.

The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.

SUBCLINICAL SEIZURES ON EEG WITH SLEEP PHASES AND CLINICAL SIGNIFICANCE IN PATIENTS WITH FOCAL EPILEPSY

Purpose: It is observed in studies that subclinical seizures have significant impact on the diagnosis, prognosis, and treatment responses. Aim of our study is investigating presence of these seizures, their relationship with sleep, contribution to diagnosis, and impact on treatment selection and prognosis in patients diagnosed with focal epilepsy. Materials and methods: Total of 1,626 EEGs conducted in the EEG unit were examined. Among them, 626 were found to belong to patients diagnosed with focal epilepsy. 140 patients who underwent twenty-minute EEG monitoring and 28 patients who underwent twenty-four-hour EEG monitoring were included in the study. Results: A comparative analysis was conducted between two cohorts of patients: one subjected to a twenty-minute EEG and the other undergoing a 24-hour EEG. In the presence of resistant epilepsy, the risk of SCS is increased by 3.1 times. The presence of SCS in frontal lobe epilepsies demonstrated a 2.2-fold elevation compared to temporal lobe epilepsies (1.0-5.3). A statistically significant relationship between Levetiracetam usage and seizures was observed (p=0.044). The calculated Odds Ratio for risk indicated a 1.2-fold (1-1.6) higher frequency of seizures with Levetiracetam usage. Risk analysis revealed a 1.5-fold (1.2-1.9) higher incidence of seizures with the use of well-known drugs in favor of lacozamide-zonisamide. Conclusion: SCSs are gaining increasing clinical significance in terms of diagnosis, prognosis, and treatment. The relationship between these sleep and SCSs holds importance for future research with a larger number of patients and centers.

Peak width of skeletonized mean diffusivity as a marker of small vessel disease in patients with temporal lobe epilepsy with hippocampal sclerosis.

White matter abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) are well known. Peak width of skeletonized mean diffusivity (PSMD) is a novel marker for quantifying white matter integrity that may reflect small vessel disease. In this study, we aimed to quantify the extent of white matter damage in patients with TLE and HS by using PSMD. We enrolled 52 patients with TLE with HS and 54 age- and sex-matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3-T magnetic resonance imaging scanner. We measured PSMD using DTI findings and compared PSMD between patients with TLE with HS and healthy controls. We also evaluated the correlation between PSMD and clinical factors in patients with TLE and HS. PSMD differed significantly between healthy controls and patients with TLE and HS, and it was higher in the patients (2.375 × 10-4 mm2/s vs. 2.108 × 10-4 mm2/s, p < .001). Furthermore, PSMD in the ipsilateral hemisphere of the HS was higher than in the contralateral hemisphere of the HS (2.472 × 10-4 mm2/s vs. 2.258 × 10-4 mm2/s, p = .040). PSMD was positively correlated with age (r = .512, p < .001) and age at seizure onset (r = .423, p = .002) in patients with TLE and HS. Patients with TLE and HS had higher PSMD values than healthy controls, and PSMD was positively correlated with age. These findings provide evidence of white matter damage probably due to small vessel disease in patients with TLE and HS and support the feasibility of PSMD as a promising imaging marker for epileptic disorders.

Seizure outcomes and associated factors in adults with unilateral mesial temporal lobe epilepsy undergoing surgery

ObjectiveTo analyze postoperative seizure outcomes and factors associated with unfavorable seizure control (Engel III-IV) in adults with drug-resistant unilateral mesial temporal epilepsy who underwent temporal lobectomy. MethodsThis was an observational, longitudinal, and retrospective study. A descriptive analysis of sociodemographic, clinical, and paraclinical characteristics was performed. The incidence rate of inadequate seizure control was calculated, and a Kaplan-Meier curve was reported. Cox regression analysis was conducted to identify factors associated with unfavorable outcomes. ResultsA total of 285 patients were included, 56.4% were women, and 49.12% underwent standard temporal lobectomy. Engel I were achieved in 70.87% of patients, while 6.31% experienced postsurgical complications. The estimated incidence rate of unfavorable outcomes was 3.87 cases per 100 person-years (95% CI: 3.51-4.27). Cox regression analysis indicated that patients with a temporal functional deficit zone, as identified by neuropsychological testing, had a 55.34% lower risk of an unfavorable outcome (adjusted HR: 0.4466, 95% CI: 0.236-0.854) compared to those with non-conclusive or extratemporal deficits. Concordance between video-electroencephalogram and brain magnetic resonance imaging findings in patients with right-sided lesions was also a protective factor (adjusted HR: 0.1868, 95% CI: 0.06-0.578). Discontinuation of anti-seizure treatment significantly increased the risk of an unfavorable outcome (adjusted HR: 6.718, 95% CI: 3.309-13.64). ConclusionTemporal lobe epilepsy surgery can achieve long-term seizure control in a significant proportion of patients. Neuropsychological assessment and concordance between MRI and video-EEG are essential presurgical factors for favorable outcomes. Additionally, patients should continue with antiepileptic treatment post-surgery to prevent seizure recurrence.

Human adult neurogenesis loss corresponds with cognitive decline during epilepsy progression.

Mesial temporal lobe epilepsy (MTLE) is a syndromic disorder presenting with seizures and cognitive comorbidities. Although seizure etiology is increasingly understood, the pathophysiological mechanisms contributing to cognitive decline and epilepsy progression remain less recognized. We have previously shown that adult hippocampal neurogenesis dramatically declines in MTLE patients with increased disease duration. Here, we investigate when multiple cognitive domains become affected during epilepsy progression and how human neurogenesis levels contribute to it. We find that intelligence, verbal learning, and memory decline at a critical period of 20 years disease duration. In contrast to rodents, the number of human immature neurons positively associates with auditory verbal, rather than visuospatial, learning and memory. Moreover, this association does not apply to mature granule neurons. Our study provides cellular evidence of how adult neurogenesis corresponds with human cognition and signifies an opportunity to advance regenerative medicine for patients with MTLE and other cognitive disorders.

Serum MicroRNAs as Predictors of Diagnosis and Drug-resistance in Temporal Lobe Epilepsy: A Preliminary Study.

Temporal lobe epilepsy (TLE) is the most common form of refractory focal epilepsy, and the current clinical diagnosis is based on EEG, clinical neurological history and neuroimaging findings. So far, there are no blood-based molecular biomarkers of TLE to support clinical diagnosis, despite the pathogenic mechanisms underlying TLE involving defects in the regulation of gene expression. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of gene expression. Recent studies show the feasibility of detecting miRNAs in body fluids; circulating miRNAs have emerged as potential clinical biomarkers in epilepsy, although the TLE miRNA profile needs to be addressed. Here, we analysed the diagnostic potential of 8 circulating miRNAs in sera of 52 TLE patients and 40 age- and sex-matched donor controls by RT-qPCR analyses. We found that miR-34a-5p, -106b-5p, -130a-3p, -146a-5p, and -19a-3p are differently expressed in TLE compared to control subjects, suggesting a diagnostic role. Furthermore, we found that miR-34a-5p, -106b-5p, -146a-5p and miR-451a could become prognostic biomarkers, being differentially expressed between drug-resistant and drug-responsive TLE subjects. Therefore, serum miRNAs are diagnostic and drug-resistance predictive molecules of TLE.

Activation of hypoactive parvalbumin-positive fast-spiking interneurons restores dentate inhibition to reduce electrographic seizures in the mouse intrahippocampal kainate model of temporal lobe epilepsy

Parvalbumin-positive (PV+) GABAergic interneurons in the dentate gyrus provide powerful perisomatic inhibition of dentate granule cells (DGCs) to prevent overexcitation and maintain the stability of dentate gyrus circuits. Most dentate PV+ interneurons survive status epilepticus, but surviving PV+ interneuron mediated inhibition is compromised in the dentate gyrus shortly after status epilepticus, contributing to epileptogenesis in temporal lobe epilepsy. It is uncertain whether the impaired activity of dentate PV+ interneurons recovers at later times or if it continues for months following status epilepticus. The development of compensatory modifications related to PV+ interneuron circuits in the months following status epilepticus is unknown, although reduced dentate GABAergic inhibition persists long after status epilepticus. We employed whole-cell patch-clamp recordings from dentate PV+ interneurons and DGCs in slices from male and female sham controls and intrahippocampal kainate (IHK) treated mice that developed spontaneous seizures months after status epilepticus to study epilepsy-associated changes in dentate PV+ interneuron circuits. Electrical recordings showed that: 1) Action potential firing rates of dentate PV+ interneurons were reduced in IHK treated mice up to four months after status epilepticus; 2) spontaneous inhibitory postsynaptic currents (sIPSCs) in DGCs exhibited reduced frequency but increased amplitude in IHK treated mice; and 3) the amplitude of IPSCs in DGCs evoked by optogenetic activation of dentate PV+ cells was upregulated without changes in short-term plasticity. Video-EEG recordings revealed that IHK treated mice showed spontaneous electrographic seizures in the dentate gyrus and that chemogenetic activation of PV+ interneurons abolished electrographic seizures. Our results suggest not only that the compensatory changes in PV+ interneuron circuits develop after IHK treatment, but also that increased PV+ interneuron mediated inhibition in the dentate gyrus may compensate for cell loss and reduced intrinsic excitability of dentate PV+ interneurons to stop seizures in temporal lobe epilepsy.

Outcome predictors in patients with temporal lobe epilepsy after temporal resective surgery

BackgroundTemporal lobe epilepsy is one of the most common types of partial epilepsy. Although surgical treatment has led to significant improvements in seizure-free rates, nearly one-third of patients still have poor seizure control after surgery. Moreover, the long-term outcome is less favorable compared to short-term outcome, with 48–58% of patients experiencing seizures five years after surgery. The aim of this study was to investigate the surgical outcomes and the predictive value of prognostic factors associated with poor surgical outcomes in temporal lobe epilepsy patients receiving surgery.MethodsWe retrospectively reviewed 94 patients undergoing temporal resective surgery in the Epilepsy Center of Guangdong Provincial Hospital of Traditional Chinese Medicine between July 2016 and July 2020. Patient information including age, gender, personal and family history, as well as preoperative and postoperative clinical data (clinical type and duration of disease) was collected.ResultsThe differences of postoperative clinical efficacy in both seizure free group and non-seizure free group patients were observed. A log-rank test was used for univariate analysis, and a Cox proportional hazard model was used for multivariate analysis. Ninety-four patients were followed up for at least 1 years. At 12 months of follow-up, 71 (75.5%) patients achieved Engel class I, 5 (5.3%) patients were classified as Engel class II, 5 (5.3%) patients were classified as Engel class III, and 13 (13.8%) patients were classified as Engel class IV. Univariate analysis and multivariate Cox regression analysis indicated that the postoperative EEG abnormalities were significantly correlated with seizure recurrence and were significant independent predictive factors, with a hazard ratio of 12.940.ConclusionsThe relapse rate in our study was similar to commonly reported overall rates in temporal lobe epilepsy patients receiving surgery. Anterior temporal lobectomy is a reliable treatment option for temporal lobe epilepsy patients. Postoperative electroencephalograph abnormalities are independent risk factors for poor surgical prognosis.

Comparison of executive function in idiopathic generalized epilepsy versus temporal lobe epilepsy

ABSTRACT Executive function (EF) deficits are common in epilepsy and impact quality of life. This study compares EF in idiopathic generalized epilepsy (IGE) and temporal lobe epilepsy (TLE) patients to healthy controls. Fifty-six IGE patients, 56 TLE patients, and 60 controls (matched by age) completed cognitive tests assessing attention, memory, learning, and verbal fluency. Both epilepsy groups performed worse than controls, with TLE patients showing significantly poorer verbal learning and memory compared to IGE patients. These findings suggest that TLE patients have more severe EF impairments, likely due to focal temporal lobe dysfunction and disruptions in EF networks.

Chemogenetic silencing of the subiculum blocks acute chronic temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common form of medically-intractable epilepsy. Subicular hyperexcitability is frequently observed with TLE, presumably caused by impaired inhibition of local excitatory neurons. Here, we evaluated the effectiveness of silencing subicular pyramidal neurons to treat a rodent model of TLE. First, we generated a chronic TLE mouse model via initial intrahippocampal kainic acid (IHKA) injection. In the chronic state after first IHKA injection, behavioral seizures and histological abnormalities were reliably observed. We then injected an adeno-associated viral (AAV) vector carrying an inhibitory chemogenetic element, hM4Di, directly into the subiculum. Eight weeks after the first IHKA injection, acute seizures were induced by giving a second dose of kainic acid (KA), which mimicked generalized tonic–clonic seizures. Herein, precise control over generalized tonic–clonic seizure onset was achieved via this two-step process. We found that chemogenetic suppression of subicular pyramidal neurons had a robust anti-epileptogenesis effect in this acute-chronic model of TLE. These data confirm a crucial role of the subiculum in the propagation of hippocampal seizures and highlight the potential for using subicular chemogenetic manipulation to treat generalized tonic–clonic seizures.

Distinct brain network structure of mesial temporal lobe epilepsy compared to that of neocortical epilepsy: functional MRI study with surgically treated patients.

Mesial temporal lobe epilepsy (mTLE) and neocortical epilepsy (NE) have different anatomo-clinical characteristics. The authors hypothesized that this may be reflected in the different functional connectivity of the epileptogenic zone between mTLE and NE. The authors, therefore, examined preoperative resting-state functional connectivity MRI with regional global connectivity (rGC) analysis for surgically treated patients. The goal of this study was to detect the different functional networks associated with the epileptogenic zone between mTLE and NE. Twenty-four patients (12 with mTLE and 12 with NE) who underwent surgery were included in the study. All patients received resting-state functional MRI preoperatively. The mean rGC and number of high-rGC or low-rGC voxels were calculated using preoperative MRI in various regions of interest including the resected area. The ratio of mean rGC in the resected area to that of the whole brain was significantly lower in mTLE patients than in NE patients. Mean rGC was significantly lower than that of the contralateral counterpart of the resected area in mTLE patients, although it was not significantly different in NE patients. Low rGC was more frequently observed in the resected area in mTLE patients than NE patients, and high rGC more frequently observed in NE than mTLE. Multivariate analysis showed that the etiology of hippocampal sclerosis, the ratio of mean rGC in the resected area to that in the whole brain, and the ratio of the number of low- and high-rGC voxels relative to the whole brain were significant factors to distinguish mTLE from NE. The authors revealed a distinct brain network structure between mTLE and NE based on rGC analysis with resting-state functional MRI. The authors' unique functional connectivity analysis may be helpful for providing landmarks for lateralization or epileptogenic zones in mTLE and NE.

An examination of seizure-free outcome and visual field deficits: Anterior temporal lobectomy versus selective amygdalohippocampectomy for temporal lobe epilepsy-a systematic review and meta-analysis for comprehensive understanding.

This study compares Selective Amygdalohippocampectomy (SAHE) and Anterior Temporal Lobectomy (ATL) for temporal lobe epilepsy (TLE), focusing on seizure control and visual field deficits (VFD). While previous research suggests potential benefits of SAHE, this meta-analysis aims to clarify the comparative effectiveness of bothprocedures. This study adhered to PRISMA guidelines, comparing seizure outcomes and VFDs between SAHE and ATL for temporal lobe epilepsy. Comprehensive data extraction and meta-analysis revealed comparable efficacy, with SAHE potentially offering advantages in VFD risk reduction. Quality assessment ensured methodological rigor. 29 studies comparing SAHE and ATL for TLE. Seizure freedom analysis encompassed 23 studies (n = 3238), showing no significant difference between SAHE and ATL (RR = 0.96, 95% CI = 0.89-1.03, P = 0.26). SAHE exhibited significantly lower visual field deficits (RR = 0.87, 95% CI = 0.78-0.97, P = 0.01). Subgroup analyses highlighted differences between transsylvian SAHE and ATL but not transcortical SAHE. No significant difference was found in seizure freedom between SAHE and ATL in patients with hippocampal sclerosis. ATL is more effective than transsylvian SAHE in achieving seizure freedom. However, no significant difference in seizure freedom was observed between transcortical SAHE and ATL. There were no notable differences in seizure outcomes between the two techniques in patients with hippocampal sclerosis. In contrast, SAHE carries a lower risk of postoperative visual field deficits compared to ATL.

Hippocampal dentate gyrus dysplasia and the risk of sudden unexpected death.

Hippocampal dentate gyral dysplasia is well-described in temporal lobe epilepsy and may be a risk factor for sudden, unexpected death in several populations: infants (sudden infant death syndrome [SIDS], sudden unexpected infant death [SUID]), toddlers (sudden unexpected death of a child [SUDC]), and epileptics (sudden unexpected death in epilepsy [SUDEP]). We examined reports and histopathological slides from autopsies performed at our institution from 2008 through 2016 to determine whether the presence or absence of any of the described forms of such dysplasias (duplications, hyperconvolutions, and granule cell dispersion, including bilamination), correlated with the causes of death. From well over 4000 autopsies, we identified 949 autopsies with a neuropathology examination by a neuropathologist. Of these, 205 cases (21.6%) had 1 or more of the described abnormalities of 1 or both dentate gyri; 87 (42.4%) of the individuals in this group of 205 autopsies had died suddenly and unexpectedly, including 29/90 (32.2%) cases of SUDEP, 17/31 (54.8%) cases of SUDC, and 51/104 (49.0%) cases of infants with SIDS or SUID. We conclude that these changes are readily recognizable by experienced neuropathologists and that because they are overrepresented in an autopsy population that died suddenly and unexpectedly, they may represent a risk factor for such outcomes.

Kainate-Induced Reorganization the Dentate Gyrus of the Hippocampus Is Accompanied by Activation of Mitochondrial Fission in the Granular Layer Neurons.

The reorganization of the dentate gyrus of the hippocampus and changes in mitochondrial fission were evaluated using the kainate model of temporal lobe epilepsy. In 28 days after administration of 0.5 μg kainic acid, disturbances in the distribution of neuronal precursors in the subgranular zone of the hippocampus, thickening of the granular layer, and an increase in the content of synaptophysin in the molecular layer were detected. The observed changes were accompanied by an increase in the content of mitochondrial fission regulator protein Drp1 (dynamin related protein) and modification of the mitochondrial network in granular neurons of the dentate gyrus. These observations indicate a significant role of Drp1 in pathological rearrangements of the hippocampus during epileptogenesis and allow considering it as a potential target for pharmacological agents.

Nucleus accumbens shell electrical lesion attenuates seizures and gliosis in chronic temporal lobe epilepsy rats.

Temporal lobe epilepsy (TLE) is the most prevalent form of epilepsy. Prior research has indicated the involvement of the nucleus accumbens shell (NAcSh) in the process of epileptogenesis, thereby implying its potential as a therapeutic target for TLE. In the present study, we investigated the antiepileptic effect of the NAcSh electrical lesion. Chronic TLE was induced by stereotactic injection of kainic acid (KA) into the hippocampus 3 weeks after KA administration, and NAcSh electrical lesions were performed. Seizures in rats were monitored by video electroencephalogram (EEG) 1 week following the NAcSh electrical lesion. Besides, the spatial memory function assessment in rats was conducted using the Morris water maze (MWM) test in the final week of the experiment. Later, hippocampal glial cell activation and neuron loss in rats were evaluated through immunohistochemistry. TLE rats subjected to NAcSh electrical lesion exhibited a significant reduction in the frequency of seizures compared to untreated TLE rats. Furthermore, NAcSh electrical lesion led to less activation of hippocampal glial cells and fewer neuronal loss in TLE rats. It is worth noting that the NAcSh electrical lesion did not cause additional memory impairment. In the present study, the NAcSh electrical lesion exhibited a definitive therapeutic effect on the chronic TLE rat model, potentially due to decreased hippocampal TLE-induced activation of glial cells and neuron loss. In conclusion, our results indicated that the NAcSh is a promising therapeutic target for TLE and possesses high potential for clinical application.

MRI-Negative Temporal Lobe Epilepsy: A Study of Brain Structure in Adults Using Surface-Based Morphological Features.

This research aimed to delve into the cortical morphological transformations in patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE-N), seeking to uncover the neuroimaging mechanisms behind these changes. A total of 29 individuals diagnosed with TLE-N and 30 healthy control participants matched by age and sex were selected for the study. Using the surface-based morphometry (SBM) technique, the study analyzed the three-dimensional-T1-weighted MRI scans of the participants' brains. Various cortical structure characteristics, such as thickness, surface area, volume, curvature, and sulcal depth, among other parameters, were measured. When compared with the healthy control group, the TLE-N patients exhibited increased insular cortex thickness in both brain hemispheres. Additionally, there was a notable reduction in the curvature of the piriform cortex (PC) and the insular granular complex within the right hemisphere. In the left hemisphere, the volume of the secondary sensory cortex (OP1/SII) and the third visual area was significantly reduced in the TLE-N group. However, no significant differences were found between the groups regarding cortical surface area and sulcal depth (p < 0.025 for all, corrected by threshold-free cluster enhancement). The study's initial findings suggest subtle morphological changes in the cerebral cortex of TLE-N patients. The SBM technique proved effective in identifying brain regions impacted by epileptic activity. Understanding the microstructural morphology of the cerebral cortex offers insights into the pathophysiological mechanisms underlying TLE.

Assessing spatial memory using the Brown Location Test: Lateralizing seizures in a presurgical cohort of patients with temporal lobe epilepsy

ObjectiveWhilst the dominant temporal lobe has a well-established role in memory, the functions of its nondominant counterpart remain enigmatic. We compared the lateralizing ability of a promising spatial memory task (Brown Location Test, BLT) to other commonly used verbal and visual memory tasks in a sample of patients with unilateral temporal lobe epilepsy (TLE). MethodsNeuropsychological data from 48 TLE patients (right n = 28 and left n = 20) were compared on several verbal and nonverbal memory tasks. Univariate logistic regression analyses were used to examine the relationship between test scores and the odds of being categorised as right or left TLE, while multivariable logistic regression and decision tree analyses were used to establish the optimal combination of cognitive measures for lateralizing the epileptogenic zone (EZ). ResultsRelative to normative expectations, the right TLE group was specifically impaired on BLT measures, whereas the left TLE group was impaired on verbal and nonverbal memory tasks. The combination of BLT Delayed Recall and Delayed Recall on the Rey Auditory Verbal Learning Task (RAVLT) was identified as optimal for correctly predicting EZ laterality (AUC = 0.79). These two variables were also optimal predictors in the decision tree analysis, correctly predicting 79% of the overall sample (AUC = 0.83). ConclusionsOur findings support the BLT as a measure of right temporal lobe function. They demonstrate its superior sensitivity compared to another commonly used nonverbal memory test (i.e., Visual Reproduction; VR) and highlight the added lateralizing value of combining both verbal and nonverbal memory measures in the neuropsychological evaluation of epilepsy surgery candidates.

Chemogenetic Breakdown of the Dentate Gate Causes Seizures and Spatial Memory Deficits.

The dentate gyrus has often been posited to act as a gate that dampens highly active afferent input into the hippocampus. Effective gating is thought to prevent seizure initiation and propagation in the hippocampus and support learning and memory processes. Pathological changes to DG circuitry that occur in temporal lobe epilepsy (TLE) can increase DG excitability and impair its gating ability which can contribute to seizures and cognitive deficits. There is evidence that TLE pathologies and seizures may independently contribute to learning and memory deficits in TLE through distinct mechanisms. These two factors are difficult to untangle since TLE pathologies can drive seizures, and seizures can worsen TLE pathologies. Here we assessed whether chemogenetically increasing dentate granule cell (DGC) excitability was enough to break down the dentate gate in the absence of TLE pathologies. We found that increasing excitability specifically in DGCs caused seizures in non-epileptic mice. Importantly, due to the modulatory nature of DREADD effects, seizures were driven by intrinsic circuit activity rather than direct activation of DGCs. These seizures resulted in a spatial memory deficit when induced after training in the spatial object recognition task and showed stereotypical patterns of activity in miniscope calcium recordings. Our results provide direct support for the dentate gate hypothesis since seizures could be induced in non-epileptic animals by artificially degrading the dentate gate with chemogenetics in the absence of epilepsy pathologies.

Pathological microcircuits initiate epileptiform events in patient hippocampal slices.

How seizures begin at the level of microscopic neural circuits remains unknown. High-density CMOS microelectrode arrays provide a new avenue for investigating neuronal network activity, with unprecedented spatial and temporal resolution. We use high-density CMOS-based microelectrode arrays to probe the network activity of human hippocampal brain slices from six patients with mesial temporal lobe epilepsy in the presence of hyperactivity promoting media. Two slices from the dentate gyrus exhibited epileptiform activity in the presence of low magnesium media with kainic acid. Both slices displayed an electrophysiological phenotype consistent with a reciprocally connected circuit, suggesting a recurrent feedback loop is a key driver of epileptiform onset. Larger prospective studies are needed, but these findings have the potential to elucidate the network signals underlying the initiation of seizure behavior.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer’s disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.