Audiogenic kindling stimulates aberrant neurogenesis, synaptopodin expression, and mossy fiber sprouting in the hippocampus of rats genetically prone to audiogenic seizures

Alexey A Kulikov; Alexandra A Naumova; Ekaterina P Aleksandrova; Margarita V Glazova; Elena V Chernigovskaya

doi:10.1016/j.yebeh.2021.108445

Audiogenic kindling stimulates aberrant neurogenesis, synaptopodin expression, and mossy fiber sprouting in the hippocampus of rats genetically prone to audiogenic seizures

Epilepsy Behav. 2021 Dec:125:108445. doi: 10.1016/j.yebeh.2021.108445. Epub 2021 Nov 24.

Authors

Alexey A Kulikov¹, Alexandra A Naumova¹, Ekaterina P Aleksandrova¹, Margarita V Glazova², Elena V Chernigovskaya¹

Affiliations

¹ Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Thorez pr., 194223 St. Petersburg, Russia.
² Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 44 Thorez pr., 194223 St. Petersburg, Russia. Electronic address: mglazova@iephb.ru.

PMID: 34837844
DOI: 10.1016/j.yebeh.2021.108445

Abstract

Temporal lobe epilepsy is associated with considerable structural changes in the hippocampus. Pharmacological and electrical models of temporal lobe epilepsy in animals strongly suggest that hippocampal reorganization is based on seizure-stimulated aberrant neurogenesis but the data are often controversial and hard to interpret. The aim of the present study was to estimate neurogenesis and synaptic remodeling in the hippocampus of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizures (AGS). In our experiments we exposed KM rats to audiogenic kindling of different durations (4, 14, and 21 AGS) to model different stages of epilepsy development. Naïve KM rats were used as a control. Our results showed that even 4 AGS stimulated proliferation in the subgranular layer of the dentate gyrus (DG) accompanied with increase in number of doublecortin (DCX)-positive immature granular cells. Elevated number of proliferating cells was also observed in the hilus indicating the enhancement of abnormal migration of neural progenitors. In contrast to the DG, all DCX-positive cells in the hilus expressed VGLUT1/2 and their number was increased indicating that seizure activity accelerates glutamatergic differentiation of ectopic hilar cells. 14-day kindling further stimulated proliferation, abnormal migration, and glutamatergic differentiation of new neurons both in the DG granular and subgranular layers and in the hilus. However, after 21 AGS increased proliferation was observed only in the DG, while the numbers of immature neurons expressed VGLUT1/2 were still enhanced in both hippocampal areas. Audiogenic kindling also stimulated sprouting of mossy fibers and enhanced expression of synaptopodin in the hippocampus indicating generation of new synaptic contacts between granular cells, mossy cells, and CA3 pyramid neurons. Thus, our data suggest that epilepsy progression is associated with exacerbation of aberrant neurogenesis and reorganization of hippocampal neural circuits that contribute to the enhancement and spreading of epileptiform activity.

Keywords: Aberrant neurogenesis; Audiogenic kindling; Hippocampus; Krushinsky-Molodkina rats; Mossy fibers; Synaptopodin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Epilepsy, Reflex*
Hippocampus
Kindling, Neurologic*
Mossy Fibers, Hippocampal
Neurogenesis
Rats
Seizures