Initiation of network bursts by Ca²⁺‐dependent intrinsic bursting in the rat pilocarpine model of temporal lobe epilepsy

Abstract

Chronically epileptic rats, produced by prior injection of pilocarpine, were used to investigate whether changes in intrinsic neuronal excitability may contribute to the epileptogenicity of the hippocampus in experimental temporal lobe epilepsy (TLE). Paired extra‐/intracellular electrophysiological recordings were made in the CA1 pyramidal layer in acute hippocampal slices prepared from control and epileptic rats and perfused with artificial cerebrospinal fluid (ACSF). Whereas orthodromic activation of CA1 neurons evoked only a single, stimulus‐graded population spike in control slices, it produced an all‐or‐none burst of population spikes in epileptic slices. The intrinsic firing patterns of CA1 pyramidal cells were determined by intrasomatic positive current injection. In control slices, the vast majority (97 %) of the neurons were regular firing cells. In epileptic slices, only 53 % the pyramidal cells fired in a regular mode. The remaining 47 % of the pyramidal cells were intrinsic bursters. These neurons generated high‐frequency bursts of three to six spikes in response to threshold depolarizations. A subgroup of these neurons (10.1 % of all cells) also burst fired spontaneously even after suppression of synaptic activity. In epileptic slices, burst firing in most cases (ca 70 %) was completely blocked by adding the Ca2+ channel blocker Ni2+ (1 mm) to, or removing Ca2+ from, the ACSF, but not by intracellular application of the Ca2+ chelater 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N′,N′‐tetra‐acetic acid (BAPTA), suggesting it was driven by a Ca2+ current. Spontaneously recurring population bursts were observed in a subset of epileptic slices. They were abolished by adding 2 μm 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione (CNQX) to the ACSF, indicating that synaptic excitation is critical for the generation of these events. All sampled pyramidal cells fired repetitively during each population burst. The firing of spontaneously active bursters anteceded the population discharge, whereas most other pyramidal cells began to fire conjointly with the first population spike. Thus, spontaneous bursters are likely to be the initiators of spontaneous population bursts in epileptic slices. The dramatic up‐regulation of intrinsic bursting in CA1 pyramidal cells, particularly the de novo appearance of Ca2+‐dependent bursting, may contribute to the epileptogenicity of the hippocampus in the pilocarpine model of TLE. These findings have important implications for the pharmacological treatment of medically refractory human TLE.

KV7/M Channels Mediate Osmotic Modulation of Intrinsic Neuronal Excitability

“…Direct potentiation of these potentials by Ca 2ϩ currents was found during postnatal development (Magee and Carruth, 1999;Chen et al, 2005;Metz et al, 2005), during epileptogenesis (Sanabria et al, 2001;Su et al, 2002;Yaari et al, 2007), and after pharmacological blockage of A-type K ϩ current in the apical dendrites (Magee and Carruth, 1999). To identify the inward currents driving hyposmotic bursting, we tested its sensitivity to Na ϩ and Ca 2ϩ channel blockers.…”

“…Thus, in CA1 pyramidal cells, lowering osmolarity markedly potentiated the spike afterdepolarization (ADP), causing regular firing neurons to convert to burst-firing mode (Azouz et al, 1997). Because bursting neurons play a pivotal role in neuronal recruitment and synchronization, this effect likely contributes to the hyposmotic enhancement of neuronal network excitability and induction of epileptic activity (Chagnac-Amitai and Connors, 1989;Jensen and Yaari, 1997;Sanabria et al, 2001;Yaari and Beck, 2002;Wittner and Miles, 2007;Yaari et al, 2007), yet the mechanisms responsible for hyposmotic spike ADP facilitation and bursting have not been elucidated.…”

Role of Persistent Sodium Current in Bursting Activity of Mouse Neocortical Networks In Vitro

“…The increased difficulty of dissecting synaptic and bursting properties in mammalian networks created considerable uncertainty as to how intrinsic and synaptic properties interact to generate rhythmic activity. This is an issue of general interest because bursting neurons exist almost everywhere in the mammalian nervous system including the thalamus, basal ganglia, spinal cord (Darbon et al 2004), medulla (Peña and Ramirez 2004), hypothalamus, olfactory bulb, ventral tegmentum, hippocampus (Sanabria et al 2001), and neocortex (Connors and Gutnick 1990;Dégen-ètais et al 2003;Istvan and Zarzecki 1994;Nowak et al 2003). Although some researchers hypothesize that these neurons are primarily responsible for the generation of rhythmic activity in areas where bursting neurons are found (for a review see Arshavsky 2003), other studies claim that bursting neurons or pacemaker activity plays no obligatory role in the generation of a given rhythmic activity.…”

Electrophysiological and morphological heterogeneity of slow firing neurons in medial septal/diagonal band complex as revealed by cluster analysis

“…Square current pulses (0.4 s duration) were injected to characterize electrophysiological properties of neurons. Intrinsic membrane properties were measured following described procedures (Henderson et al, 2001,Sanabria et al, 2001. Passive intrinsic properties included resting membrane potential (RMP), input membrane resistance (Rm), and membrane time constant (τm).…”