Synaptic Remodeling of Entorhinal Input Contributes to an Aberrant Hippocampal Network in Temporal Lobe Epilepsy

Janz, Philipp; Savanthrapadian, Shakuntala; Häussler, Ute; Kilias, Antje; Nestel, Sigrun; Kretz, Oliver; Kirsch, Matthias; Bartos, Marlene; Egert, Ulrich; Haas, Carola A.

doi:10.1093/cercor/bhw093

Cited by 56 publications

(81 citation statements)

References 97 publications

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“…However, these studies addressed diffusivity changes in the whole hippocampus, disregarding the differential effects of neuronal reorganization in hippocampal subfields (Janz et al, 2017). Consistent with this notion, we found an opposing trend of FA values for the CA1 region and the DG in resected hippocampi from mTLE patients with high Wyler grades.…”

Section: Discussionmentioning

confidence: 99%

Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy

Janz

Schwaderlapp

Heining

et al. 2017

eLife

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Mesial temporal lobe epilepsy (mTLE) is the most common focal epilepsy in adults and is often refractory to medication. So far, resection of the epileptogenic focus represents the only curative therapy. It is unknown whether pathological processes preceding epilepsy onset are indicators of later disease severity. Using longitudinal multi-modal MRI, we monitored hippocampal injury and tissue reorganization during epileptogenesis in a mouse mTLE model. The prognostic value of MRI biomarkers was assessed by retrospective correlations with pathological hallmarks Here, we show for the first time that the extent of early hippocampal neurodegeneration and progressive microstructural changes in the dentate gyrus translate to the severity of hippocampal sclerosis and seizure burden in chronic epilepsy. Moreover, we demonstrate that structural MRI biomarkers reflect the extent of sclerosis in human hippocampi. Our findings may allow an early prognosis of disease severity in mTLE before its first clinical manifestations, thus expanding the therapeutic window.DOI: http://dx.doi.org/10.7554/eLife.25742.001

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Section: Discussionmentioning

confidence: 99%

Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy

Janz

Schwaderlapp

Heining

et al. 2017

eLife

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“…CFs are ubiquitous in the brain and it is well-known that they contribute to FA decreases in some regions more than others. In the medial temporal lobe, the PHC is crossed by fibers of the perforant path and adjacent pathways, which run from the entorhinal cortex into the hippocampus 38 and are known to be affected in TLE 39 . Figure 4 shows a voxel taken from the PHC in a patient and control.…”

Section: Discussionmentioning

confidence: 99%

Restriction spectrum imaging reveals decreased neurite density in patients with temporal lobe epilepsy

et al. 2016

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Objective Diffusion tensor imaging (DTI) has become a popular tool for delineating the location and extent of white matter injury in temporal lobe epilepsy (TLE). However, DTI yields nonspecific measures that are confounded by changes occurring within both the intracellular and extracellular environments. This study investigated whether an advanced diffusion method, restriction spectrum imaging (RSI) could provide a more robust measure of white matter injury in TLE relative to DTI due to RSI’s ability to separate intra-axonal diffusion (i.e., neurite density; ND) from diffusion associated with extra-axonal factors (e.g., inflammation; crossing fibers). Methods RSI and DTI scans were obtained on 21 patients with TLE and 11 age-matched controls. RSI-derived maps of ND, isotropic hindered (IH) and free (IF) water, and crossing fibers (CF) were compared to DTI-derived fractional anisotropy (FA) maps. Voxelwise and tract-based analyses were performed comparing patients with TLE to controls on each diffusion metric. Results Reductions in FA were seen primarily in frontotemporal white matter in TLE and were most pronounced proximal to the seizure focus. Reductions in ND corresponded to those seen in the FA maps; however, ND reductions were greater in magnitude, more lateralized to the epileptogenic hemisphere, and showed a broader pattern. Increases in IF/IH and effects from CFs also contributed to reduced FA in the ipsilateral parahippocampal cingulum and fornix, with decreases in IH extending into extratemporal regions. Reduced ND of the uncinate fasciculus was associated with longer disease duration, whereas FA was not associated with any clinical variables. Significance RSI may provide a more specific measure of white matter pathology in TLE, distinguishing regions primarily affected by axonal/myelin loss from those where CFs and increases in extracellular water also play a role. By providing a more specific measure of axonal/myelin loss, RSI-derived ND may better reflect overall white matter burden in epilepsy.

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“…13,20,21 To determine basic principles of MTLE, we investigated whether granule cells and CA2 PCs share similar molecular properties during epileptogenesis. We used the intrahippocampal KA mouse model, which reproduces major characteristics of the human pathology, including chronic, mostly subclinical EA, hippocampal sclerosis, GCD, and mossy fiber sprouting 16,17,[22][23][24] with survival of dentate granule cells and CA2 PCs. 12 We performed a detailed time course analysis of Bdnf mRNA expression during epileptogenesis and tested for correlation with EA by recording both regions in vivo.…”

Section: Introductionmentioning

confidence: 99%

Expression of brain‐derived neurotrophic factor and structural plasticity in the dentate gyrus and CA2 region correlate with epileptiform activity

2019

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Objective Hippocampal sclerosis is a hallmark of mesial temporal lobe epilepsy (MTLE), comprising gliosis and neuronal loss in the hippocampus. However, dentate granule cells and CA2 pyramidal cells (PCs) survive, as they share physiological characteristics that may render them less sensitive to hyperexcitation in MTLE. Here, we asked whether both engage similar molecular plasticity mechanisms to support their resilience in MTLE. We chose brain‐derived neurotrophic factor (BDNF), correlated the expression with activity, and used neuropeptide Y (NPY) and principal cell dispersion as plasticity readout. Methods Adult male mice received a unilateral intrahippocampal kainate injection to induce status epilepticus (SE) and bilateral electrodes into the dentate gyrus and CA2 for in vivo recordings and quantification of epileptiform activity. To assess the time course of Bdnf mRNA expression in these regions, we performed fluorescence in situ hybridization, complemented by immunohistochemistry for NPY and quantification of principal cell dispersion. Results We show that Bdnf expression was transiently up‐regulated during SE in the granule cell layer (GCL) and CA2 and, after a slight reduction at 2 days, increased persistently in both regions ipsilaterally. Intrahippocampal recordings revealed a threshold for the duration of SE to induce these changes. Recurrent epileptiform activity developed in the ipsilateral dentate gyrus and CA2 over time and was correlated with Bdnf mRNA levels, although more pronounced in the dentate gyrus. The dispersion of the GCL and CA2 correlated with Bdnf mRNA expression. NPY protein expression was only increased in granule cells and mossy fibers, remaining unchanged in CA2. Significance Our study reveals differential molecular plasticity changes in granule cells and CA2 PCs despite many similarities (epileptiform activity, somatic mossy fiber input, dispersion). These findings contribute to the understanding of common as well as individual characteristics of the cell populations underlying the epileptic hippocampal network.

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Synaptic Remodeling of Entorhinal Input Contributes to an Aberrant Hippocampal Network in Temporal Lobe Epilepsy

Cited by 56 publications

References 97 publications

Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy

Early tissue damage and microstructural reorganization predict disease severity in experimental epilepsy

Restriction spectrum imaging reveals decreased neurite density in patients with temporal lobe epilepsy

Expression of brain‐derived neurotrophic factor and structural plasticity in the dentate gyrus and CA2 region correlate with epileptiform activity

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