Septo-hippocampal networks in chronic epilepsy

https://doi.org/10.1016/j.expneurol.2009.12.010Get rights and content

Abstract

The medial septum inhibits the appearance of interictal spikes and seizures through theta rhythm generation. We have determined that medial septal neurons increase their firing rates during chronic epilepsy and that the GABAergic neurons from both medial and lateral septal regions are highly and selectively vulnerable to the epilepsy process. Since the lateral septal region receives a strong projection from the hippocampus and its neurons are vulnerable to epilepsy, their functional properties are probably altered by this disorder. Using the pilocarpine model of temporal lobe epilepsy we examined the pilocarpine-induced functional alterations of lateral septal neurons and provided additional observations on the pilocarpine-induced functional alterations of medial septal neurons. Simultaneous extracellular recordings of septal neurons and hippocampal field potentials were obtained from chronic epileptic rats under urethane anesthesia. Our results show that: (1) the firing rates of lateral septal neurons were chronically decreased by epilepsy, (2) a subset of lateral septal neurons increased their firing rates before and during hippocampal interictal spikes, (3) the discharges of those lateral septal neurons were well correlated to the hippocampal interictal spikes, (4) in contrast, the discharges of medial septal neurons were not correlated with the hippocampal interictal spikes. We conclude that epilepsy creates dysfunctional and uncoupled septo-hippocampal networks. The elucidation of the roles of altered septo-hippocampal neuronal populations and networks during temporal lobe epilepsy will help design new and effective interventions dedicated to reduce or suppress epileptic activity.

Introduction

Temporal lobe epilepsy is the most frequent type of epilepsy in humans (Engel, 2001). Due to the scarcity and variability of human tissue from epileptic patients, the investigation of mechanisms underlying the generation of epileptic activity mostly relies on the use of animal models. The pilocarpine animal model is one the most widely used and accepted models of temporal lobe epilepsy (Cavalheiro, 1995, Leite et al., 1990, Leite and Cavalheiro, 1995, Lemos and Cavalheiro, 1995).

The elucidation of the pathophysiology of epilepsy requires the identification of the neurons involved in both the production of epileptic activity and its control. We have established that the medial septal region, through its role in hippocampal theta rhythm (θ) production, exerts a strong antiepileptic effect in chronic epileptic rats produced by systemic pilocarpine injection (Colom et al., 2006). The work of Lerma and Miller using penicillin, pentylenetetrazol and electrically induced epilepsy (kindling) demonstrates that the hippocampal theta rhythm state corresponded to a seizure-and interictal spike-resistant condition (Lerma et al., 1984, Miller et al., 1994). The recent work of Kitchiniga and Butuzova shows that theta oscillations, either spontaneous or evoked by sensory stimulation, abolish epileptiform activity in kindled rabbits (Kitchigina and Butuzova, 2009). Experimental evidence also indicates that septal cholinergic neurons exert an antiepileptic effect in hippocampal kindled rats (Ferencz et al., 2001). However, the septo-hippocampal networks participating in epilepsy production and control remain to be established. This determination of epileptic networks and control mechanisms is important to create (1) new therapeutic targets and (2) computer and mathematical models that can be used to predict the evolution of the disease (Lytton 2008).

The medial septum sends cholinergic, GABAergic and glutamatergic projections to the hippocampus (Colom et al., 2005, Colom, 2006). In turn, the hippocampus projects back to the medial and lateral septal structures. While a small hippocampo-medial septal projection appears to be GABAergic (Tóth et al., 1993), the main hippocampo-septal projection terminates on lateral septal neurons, is excitatory, and uses glutamate as neurotransmitter (Meibach and Siegel, 1977, Stevens and Cotman, 1986). Typically it has been considered that the septo-hippocampal loop is closed by a latero-medial septal projection. While the presence of this projection has been questioned (Leranth et al., 1992), more recent work clearly identified latero-medial septal projections (Risold and Swanson, 1997). Thus, the lateral septum is probably affected by the hippocampal epileptic discharges and transmits the epilepsy-induced changes to the medial septal region. We have found that in chronic epileptic rats the group of rhythmically bursting firing medial septal neurons significantly increased their firing rates in relation to controls (from 13.86 to 29.14 spikes/s; Colom et al., 2006). This finding could be explained by decreases in the firing rates of the lateral septal GABAergic neurons that project to the medial septal region. In this study, we examined the epilepsy-induced alterations of lateral septal neuron firing repertoires and the relationship between medial septal, lateral septal and hippocampal changes.

Section snippets

Model of temporal lobe epilepsy induced by systemic pilocarpine administration

Twelve young Sprague–Dawley rats (100–150 g at the beginning of this experiment) were used for this study. Additionally, medial septum recordings obtained from twenty-four pilocarpine-treated rats, used in previous work (Colom et al., 2006), were subjected to further analysis. Rats were maintained in controlled conditions 12 h/12 h light/dark cycle with food and water ad libitum. All animal experimentation was conducted in accordance with IACUC guidelines and with The National Institutes of

Hippocampal theta rhythm

Septo-hippocampal synchronizing mechanisms were weakened but still functional in chronic epileptic rats. All epileptic animals (7 rats) showed a hippocampal theta rhythm with reduced amplitude but still clearly detectable (compare Fig. 1A to Fig. 1B). These epilepsy-induced theta rhythm alterations have been previously described (Colom et al., 2006).

Lateral septal neurons

Forty-one lateral septal neurons were recorded from each group (control and chronic epileptic rats). Lateral septal neurons recorded from chronic

Discussion and conclusions

The frequent failure to successfully treat temporal lobe epilepsy is probably due to our lack of understanding of: (1) epileptogenesis, (2) epilepsy-induced alterations of brain networks and (3) roles of altered neuronal populations and circuits in both epilepsy generation and control. This work and previous studies from our laboratory aimed to clarify those issues (Colom et al., 2006, Garrido-Sanabria et al., 2006).

Septal neurons modulate the activity of hippocampal and neocortical circuits

Acknowledgments

NIH: SC1N2063950 (National Institute of General Medical Sciences/National Institute of Neurological Disorders and Strokes), P20MD001091 (National Center on Minority Health and Health Disparities) and 5R25GM83755-2 (Division of Minority Opportunities in Research, National Institute of General Medicine).

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