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Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy.

ABSTRACT: Reprogramming brain-resident glial cells into clinically relevant induced neurons (iNs) is an emerging strategy toward replacing lost neurons and restoring lost brain functions. A fundamental question is now whether iNs can promote functional recovery in pathological contexts. We addressed this question in the context of therapy-resistant mesial temporal lobe epilepsy (MTLE), which is associated with hippocampal seizures and degeneration of hippocampal GABAergic interneurons. Using a MTLE mouse model, we show that retrovirus-driven expression of Ascl1 and Dlx2 in reactive hippocampal glia in situ, or in cortical astroglia grafted in the epileptic hippocampus, causes efficient reprogramming into iNs exhibiting hallmarks of interneurons. These induced interneurons functionally integrate into epileptic networks and establish GABAergic synapses onto dentate granule cells. MTLE mice with GABAergic iNs show a significant reduction in both the number and cumulative duration of spontaneous recurrent hippocampal seizures. Thus glia-to-neuron reprogramming is a potential disease-modifying strategy to reduce seizures in therapy-resistant epilepsy.

SUBMITTER: Lentini C

PROVIDER: S-EPMC8657801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mesial temporal lobe epilepsy is the most common type of focal epilepsy and in its course often becomes refractory to anticonvulsant pharmacotherapy. A resection of the mesial temporal lobe structures is a promising option in these cases. However, approximately 30% of all patients remain with persistent seizures after surgery. In other words, reliable criteria for patients' outcome prediction are absent. To address this limitation, we investigated pre-surgical brain morphology of patients with unilateral left mesial temporal lobe epilepsy who underwent a selective amygdalohippocampectomy. Using support vector classification, we aimed to predict the post-surgical seizure outcome of each patient based on the pre-surgical T1-weighted structural brain images. Due to morphological gender differences and the evidence that men and women differ in onset, prevalence and symptomology in most neurological diseases, we investigated male and female patients separately. Thus, we benefitted from the capability to validate the reliability of our method in two independent samples. Notably, we were able to accurately predict the individual patients' outcome in the male (94% balanced accuracy) as well as in the female (96% balanced accuracy) group. In the male cohort relatively larger white matter volumes in the favorable as compared to the non-favorable outcome group were identified bilaterally in the cingulum bundle, fronto-occipital fasciculus and both caudate nuclei, whereas the left inferior longitudinal fasciculus showed relatively larger white matter volume in the non-favorable group. While relatively larger white matter volumes in the female cohort in the left inferior and right middle longitudinal fasciculus were associated with the favorable outcome, relatively larger white matter volumes in the non-favorable outcome group were identified bilaterally in the superior longitudinal fasciculi I and II. Here, we observed a clear lateralization and distinction of structures involved in the classification in men as compared to women with men exhibiting more alterations in the hemisphere contralateral to the seizure focus. In conclusion, individual post-surgical outcome predictions based on a single T1-weighted magnetic resonance image seem plausible and may thus support the routine pre-surgical workup of epilepsy patients.

Project description:The epilepsies represent one of the most common neurological disorders. Mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent resistance to anti-epileptic drugs thus representing a major health care problem. In TLE, the origin of seizure activity typically involves the hippocampal formation, which displays major neuropathological features, described with the term hippocampal sclerosis (HS). HS is the most frequent pathological substrate of refractory mesial temporal lobe epilepsy. Complex partial seizures (CPS) are the predominant seizure type associated with medial temporal lobe epilepsy. MTLE is commonly due to mesial temporal sclerosis (MTS). The biology underlying the epilepstic seizures and the transcriptome associated to the seizure in intractable medial temporal lobe epilepsy is ill understood. The aim of the study was to identify potential biomarkers that could identify epileptic seizure. Thus we performed transcriptome profiling of ten medial temporal lobe epilepsy cases which are resistant to the drug and underwent temporal lobectomy. The cases constitutes of patients with intractable complex partial seizure, treated medically and have undergone detailed presurgical evaluation and subjected to surgery for standard temporal lobectomy and amygdalo-hippocampectomy. The spiking areas identified after the electrocorticography will form the test tissues, which compared with the nonspiking areas removed during the surgery, from the same patient. This could probably form one of the appropriate controls, as test and control are from same patient, which eliminates the genome variations that could incur due to the comparison with the tissues from the another patient. Also this could get rid of expression changes due to the treatments undergone by the patient. We performed two color microarray wherein we labled seizure focus (spiking area) with Cy5 and non-seizure region tissues (non-spiking) with Cy3. As a strategy to test the possibility of potential diagnostic biomarkers we are intended to test the differentially regulated molecules in an independent set of epilepsy samples. Two color experiment

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Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy.

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