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

Abstract

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.

Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy

“…Following KA injection the occurrence of a behavioral SE was verified. SE was characterized by mild convulsion, chewing, immobility, or rotations, as described before (Riban et al, 2002;Tulke et al, 2019). Mice that did not have SE (n=5) or died due to KA treatment (n=18) or surgical procedures (n=2) were excluded from further experiments.…”

“…Slices were hybridized with DIG-labeled antisense cRNA probes and immunodetection of the DIG-labeled hybrids was performed with a peroxidaseconjugated anti-DIG antibody (1:2000; raised in sheep; Roche Diagnostics, Mannheim, Germany). The fluorescence signal was developed with tyramide signal amplification (TSA) Plus Cyanine 3 System kit (PerkinElmer, Waltham, Massachusetts, USA) as described previously (Tulke et al, 2019).…”

Mossy fiber sprouting into the hippocampal region CA2 in patients with temporal lobe epilepsy

“…The underlying cause of MFS into the CA2 region is yet to be determined. MF could be attracted through increased expression of neurotrophins like brain‐derived neurotrophic factor (BDNF; Mathern, Babb, Micevych, Blanco, & Pretorius, 1997; Heinrich et al, 2011), which is upregulated in the CA2 region of intrahippocampally KA‐injected mice (Tulke, Haas, & Häussler, 2019). The striking similarity of our findings in human specimens and in mice makes the latter an appropriate system to determine underlying mechanisms of the phenomena observed in humans and the translational importance of comparing characteristics of human specimens and mouse tissue.…”

In vivocharacterization and application of a novel potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus

“…Using a Nanoject III (Drummond Scientific Company, Broomall, Pennsylvania, USA), 50 nL of 0.9% sterile saline or 15 mM kainate (Tocris, Bristol, UK) was stereotaxically injected into the left dorsal dentate gyrus (DG) at coordinates relative to bregma: anterioposterior (AP) = −2.0 mm, mediolateral (ML) = −1.5 mm, and relative to the cortical surface: dorsoventral (DV) = −1.5 mm. Following kainate injection, the occurrence of behavioral status epilepticus was verified by observation of mild convulsion, chewing, immobility, or rotations, as described before (Riban et al, 2002; Tulke et al, 2019). Ten mice died as a consequence of status epilepticus and further two were excluded due extreme hippocampal atrophy (Table 1).…”