Drebrin expression patterns in patients with refractory temporal lobe epilepsy and hippocampal sclerosis

Abstract

Objective: Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. Methods: Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n = 33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n = 20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Doublelabeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. Results: Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrinpositive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower 1582 | DOMBROSKI et al. 1 | INTRODUCTION Up to 30% of temporal lobe epilepsy (TLE) patients have drug-resistant seizures with variable frequency and significant cognitive and memory deficits. 1,2 For drug-resistant TLE cases, surgical resection of temporal lobe structures is recommended for seizure control. 3,4 During epileptogenesis (ie, between the initial injury and seizure recurrence), several plastic changes occur in the hippocampal formation, culminating with the establishment of hippocampal sclerosis (HS). 5 HS is characterized by neuron loss, often severe in

The actin binding protein drebrin helps to protect against the development of seizure-like events in the entorhinal cortex

“…These findings suggest that epilepsy patients have less stable actin filaments within their spines. In line with this, a recent study found that lower drebrin levels in the hippocampi of temporal lobe epilepsy patients were associated with higher seizure frequency and less neuron survival 17 . These dendritic changes may represent a trait in the pathophysiology of seizure development or a consequence of them or even a compensatory response as a form of homeostatic plasticity to dampen excessive neuronal excitability 14 .…”

“…The initial reduction was followed by the recovery of drebrin levels in the chronic phase of pilocarpine-induced seizures suggesting the crucial role of drebrin in reactive synaptic plasticity 18 , 19 . Another recent study, showed a negative correlation between drebrin expression and seizure frequency in particular in the dentate gyrus 17 . Taken together it is difficult to conclude on a linear correlation between drebrin expression and seizure susceptibility.…”

“…Decreased levels of drebrin in the brain were shown in states with high epilepsy prevalence 14 such as Alzheimer’s disease 15 and Down's syndrome 16 and a lower drebrin level in the hippocampi of temporal lobe epilepsy patients was associated with more frequent seizures 17 . Decrease and reactivation of drebrin expression in post-status epilepsy models have been described already 18 – 20 , but it still remains unclear whether the changes are pro- or antiepileptogenic and if they are the consequence of the seizures or play a role in the epileptogenesis.…”

Editorial: Psychiatric Comorbidities in the Epilepsies: Extensive Mechanisms and Broad Questions

“…They also studied whether neuron density differs between TLE patients with and without depression. Their study follows up on previous reports on histopathological differences between patients with and without psychiatric comorbidities in general (Kandratavicius et al, 2012a(Kandratavicius et al, , 2014(Kandratavicius et al, , 2015 and between types of hippocampal sclerosis and epilepsy-related factors (Coras et al, 2014;Thom, 2014;Rodrigues et al, 2015;Dombroski et al, 2020).…”

Histological correlates of hippocampal magnetization transfer images in drug-resistant temporal lobe epilepsy patients

“…Even if more HS type 1 cases where added, we believe stronger associations would emerge. Apart from HS types, we know that even the same HS type can had differential synaptic reorganization in several regions ( Dombroski et al, 2020 ). It would be interesting to see if these, changes could impact MTR in higher field MRI, with smaller voxel sizes and subfield MTR assessment.…”