Septo-Hippocampal Networks in Chronically Epileptic Rats: Potential Antiepileptic Effects of Theta Rhythm Generation

Abstract

A series of experiments was carried out testing the hypothesis that the septal region decreases the hippocampal susceptibility to hyperexcitability states through theta rhythm generation. Medial septal neurons were simultaneously recorded with hippocampal field potentials to investigate the septo-hippocampal function in the pilocarpine model of chronic epilepsy. The theta rhythm from chronically epileptic rats had lower amplitude (20% less) and higher frequency than controls (from 3.38 to 4.25 Hz), suggesting that both generator and pacemaker structures are affected during the epileptic process. At the cellular level, the group of rhythmically bursting firing medial septal neurons, in the epileptic animals, significantly and chronically increased their firing rates in relation to controls (from 13.86 to 29.14 spikes/s). Peristimulus histograms performed around hippocampal sharp waves showed that all high-frequency firing neurons, including rhythmically bursting neurons and most slow firing neurons, decreased firing rates immediately after hippocampal epileptic discharges. Thus inhibitory hippocampo-septal influences prevail during hippocampal epileptic discharges. The occurrence of epileptic discharges was reduced 86-97% of the number observed during spontaneous theta and theta induced by sensory (tail pinch) or chemical stimulation (carbachol), suggesting that the presence of the theta state regardless of how it was produced was responsible for the reduction in epileptic discharge frequency. The understanding of the theta rhythm "anti-epileptic" effect at the cellular and molecular levels may result in novel therapeutic approaches dedicated to protect the brain against abnormal excitability states.

Theta Rhythmopathy as a Cause of Cognitive Disability in TLE

“…A large body of literature demonstrates a substantial decrease in hippocampal theta oscillation power and a small decrease in peak theta frequency in multiple rodent models of TLE (34)(35)(36)(37)(38)(39)(40)(41)(42). In addition to loss of power, theta oscillations are less coherent within the hippocampus, with a clear loss of theta coherence demonstrated between regions receiving temporoammonic and perforant path entorhinal inputs, mainly in proximal locations (closer to CA3) (40).…”

Septal nuclei enlargement in human temporal lobe epilepsy without mesial temporal sclerosis

“…A potential explanation comes from animal studies demonstrating that septal cholinergic neurons are resistant to seizure-induced neuronal loss 8,17 and may actually enlarge in TLE via a mechanism dependent upon nerve growth factor (NGF) released from hippocampus and transported to septal nuclei retrogradely along the fornix. 18,19 NGF is an essential growth factor for septal cholinergic neurons, and its production is highly upregulated by hippocampal seizures.…”

“…2,3 In animal models of temporal lobe epilepsy (TLE), medial septal lesions facilitate epileptogenesis, and chemical or electrical septal stimulation can stop and prevent seizures. [4][5][6][7][8] To our knowledge, no studies have examined septal nuclei structure in human TLE.…”

Functional changes in the septal GABAergic system of animals with a model of temporal lobe epilepsy

“…It is possible that the increase in the number of neurons operating in the rhythmic mode in the MSDB of the epileptic brain is of adaptive significance; thus, it was shown that theta-oscillations fulfill the protective function in the animals with the models of TLE (Miller et al 1994;Ferencz et al 2001;Colom et al 2006;Kitchigina and Butuzova 2009). The results of the study give a deeper insight into the mechanisms of epileptogenesis and contribute to the development of new approaches to the treatment of TLE.…”