Research PaperRole of CA3 theta-modulated interneurons during the transition to spontaneous seizures
Introduction
Understanding changes in neuronal firing patterns during the transition to seizures is essential for understanding epilepsy and for developing therapeutic interventions. Multiple studies show that during the transition to seizures, some neurons increase their firing rate while others decrease, (Babb et al., 1987, Bower and Buckmaster, 2008, Bower et al., 2012, Truccolo et al., 2011) suggesting heterogeneous changes in firing rate. CA3 subfield is a particularly interesting structure within the hippocampus because while it is reported to be a common site of seizure initiation in pilocarpine-treated rats (Lévesque et al., 2012), we recently showed that prior to seizure onset, pyramidal cells are at best firing more slowly and only increase their firing rates after the onset of rhythmic LFP spiking (Grasse et al., 2013). Moreover, approximately 40% of CA3 interneurons increase their firing rate at onset (Grasse et al., 2013) and Toyoda et al. (2015) demonstrated that these cells are predominately theta-on interneurons. These results suggest that identifying the neuronal subtypes could be critical to understanding the physiological mechanisms underlying the transition to seizures.
Neuronal subtypes, identified by their firing patterns in relation to theta rhythms, might be particularly important because there is mounting evidence that theta oscillations are dominant in the hippocampus and medial septum prior to chemically induced seizures (Butuzova and Kitchigina, 2008, Kitchigina and Butuzova, 2009) and spontaneous seizures (Grasse et al., 2013). In fact, a recent study reported that theta oscillations preceded a majority (81%) of spontaneous seizures in a rat model of epilepsy (Sedigh-Sarvestani et al., 2014). These studies emphasize the potential role of theta oscillations during the transition to seizures. Unlike in epileptic animals, neuronal firing during theta oscillations in healthy animals is widely studied (Buzsáki, 2002, Csicsvari et al., 1999). Within temporal lobe structures, both interneurons and pyramidal cells can be further classified by changes in their firing patterns during theta periods. Studies in anesthetized animals identified a subtype of neurons whose firing rate increased during theta oscillations (theta-on) compared to non-theta periods and a subtype whose firing rate decreased (theta-off cells) (Bland et al., 1999, Colom and Bland, 1987, Smythe et al., 1991) and these subtypes are differentially modulated at the transition to seizure (Toyoda et al., 2015).
Despite recent evidence of changes in firing patterns of theta-related cell types during theta epochs transitioning to seizure onset, it is unclear whether neuronal firing patterns during interictal theta oscillations in epilepsy are fundamentally different from those in healthy controls. Moreover, it is unknown whether the theta oscillations that precede seizures are different from those during interictal theta oscillations. To address these questions, theta oscillations and the underlying neuronal firing patterns were compared between control rats and epileptic (pilocarpine model of temporal lobe epilepsy) rats during interictal and preictal periods. Results show that theta and neuronal firing patterns in epileptic animals are distinctly different from those in healthy control animals, suggesting long-term changes that impact the CA3 network during interictal periods as well as preictal periods.
Section snippets
Overview
Animals were injected with pilocarpine to induce status epilepticus for 2 h and monitored until they exhibited chronic spontaneous seizures. Pilocarpine-treated rats (N = 6) with spontaneous seizures and naive age-matched control rats (N = 4) were implanted with drivable tetrodes in CA3 hippocampus. Wide band neural signals and video recordings were obtained for multiple 48 h recording sessions in each animal. Seizure frequency was variable and seizures sometimes occurred in clusters, but overall
Theta oscillations precede majority of seizures
A total of 25 spontaneous seizures were recorded from 6 Long-Evans rats. In the 2 min prior to rhythmic ictal spiking onset, most seizures were preceded by theta oscillations (84%) that occurred in small bursts (duration 4.3 ± 1.9 s, Fig. 2A, B). To determine if this theta was associated with REM sleep as previously described (Sedigh-Sarvestani et al., 2014), we classified the behavior of the animals and determined that 14 seizures were preceded by sleep, 8 were preceded by awake stationary
Discussion
While our data support earlier studies demonstrating that theta oscillations are likely to be dominant during the transition to seizures (Butuzova and Kitchigina, 2008, Fujita et al., 2014, Kitchigina and Butuzova, 2009, Kitchigina et al., 2013, Sedigh-Sarvestani et al., 2014) and that theta-on interneurons selectively increase their firing rate, our comparisons of neuronal activity from healthy controls and epileptic animals identified important differences describing the impact of epilepsy on
Acknowledgements
We would like to thank Dr. Liset Menendez de la Prida for feedback on earlier versions of the paper and Dr. Beatriz Gal for performing histological staining of sections used in the paper. This work was supported by a grant from Coulter Foundation.
References (83)
- et al.
Interneuron control of hippocampal oscillations
Curr. Opin. Neurobiol.
(2015) - et al.
Evidence for separate projections of hippocampal pyramidal and non-pyramidal neurons to different parts of the septum in the rat brain
Neurosci. Lett.
(1982) - et al.
GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity
Prog. Neurobiol.
(2011) - et al.
Firing patterns of human limbic neurons during stereoencephalography (SEEG) and clinical temporal lobe seizures
Electroencephalogr. Clin. Neurophysiol.
(1987) - et al.
Heterogeneity among hippocampal pyramidal neurons revealed by their relation to theta-band oscillation and synchrony
Exp. Neurol.
(2005) - et al.
Repeated blockade of GABAA receptors in the medial septal region induces epileptiform activity in the hippocampus
Neurosci. Lett.
(2008) Theta oscillations in the hippocampus
Neuron
(2002)- et al.
State-dependent spike train dynamics of hippocampal formation neurons: evidence for theta-on and theta-off cells
Brain Res.
(1987) - et al.
Multiple facets of GABAergic neurons and synapses: multiple fates of GABA signalling in epilepsies
Trends Neurosci.
(2005) - et al.
Reliability and state dependence of pyramidal cell-interneuron synapses in the hippocampus: An ensemble approach in the behaving rat
Neuron
(1998)
The pilocarpine model of temporal lobe epilepsy
J. Neurosci. Methods
Septo-hippocampal networks in chronic epilepsy
Exp. Neurol.
Neuronal synchrony and the transition to spontaneous seizures
Exp. Neurol.
Status epilepticus induces increasing neuronal excitability and hypersynchrony as revealed by optical imaging
Neurobiol. Dis.
Immunocytochemical characterization of hippocamposeptal projecting GABAergic nonprincipal neurons in the mouse brain: a retrograde labeling study
Brain Res.
Fast spiking cells in rat hippocampus (CA1 region) contain the calcium-binding protein parvalbumin
Brain Res.
Theta activity of septal neurons during different epileptic phases: the same frequency but different significance?
Exp. Neurol.
Disturbances of septohippocampal theta oscillations in the epileptic brain: reasons and consequences
Exp. Neurol.
Preictal state identification by synchronization changes in long-term intracranial EEG recordings
Clin. Neurophysiol.
Epileptic seizures may begin hours in advance of clinical onset: a report of five patients
Neuron
Temporally structured replay of awake hippocampal ensemble activity during rapid eye movement sleep
Neuron
Impaired and repaired inhibitory circuits in the epileptic human hippocampus
Trends Neurosci.
H channel-dependent deficit of theta oscillation resonance and phase shift in temporal lobe epilepsy
Neurobiol. Dis.
Classification of patterns of EEG synchronization for seizure prediction
Clin. Neurophysiol.
Cortical abnormalities in epilepsy revealed by local EEG synchrony
NeuroImage
Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm
Neuron
The role of chloride-dependent inhibition and the activity of fast-spiking neurons during cortical spike-wave electrographic seizures
Neuroscience
Hippocampal EEG and behavior: changes in amplitude and frequency of RSA (theta rhythm) associated with spontaneous and learned movement patterns in rats and cats
Behav. Biol.
Spatio-temporal patient–individual assessment of synchronization changes for epileptic seizure prediction
Clin. Neurophysiol.
Brain state dependent postinhibitory rebound in entorhinal cortex interneurons
J. Neurosci.
Hippocampo-septal fibers terminate on identified spiny neurons in the lateral septum: a combined Golgi/electron-microscopic and degeneration study in the rat
Cell Tissue Res.
Responses of the superficial entorhinal cortex in vitro in slices from naive and chronically epileptic rats
J. Neurophysiol.
Mechanisms of neural synchrony in the septohippocampal pathways underlying hippocampal theta generation
J. Neurosci.
Changes in granule cell firing rates precede locally recorded spontaneous seizures by minutes in an animal model of temporal lobe epilepsy
J. Neurophysiol.
Spatiotemporal neuronal correlates of seizure generation in focal epilepsy
Epilepsia
Analysis of initial slow waves (ISWs) at the seizure onset in patients with drug resistant temporal lobe epilepsy
Epilepsia
Depth profiles of hippocampal rhythmic slow activity (‘theta rhythm’) depend on behaviour
Electroencephalography
Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy
J. Physiol.
Driving fast-spiking cells induces gamma rhythm and controls sensory responses
Nature
The pilocarpine model of epilepsy
The Italian Journal of Neurological Sciences
Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy
Nat. Neurosci.
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2019, Neurobiology of DiseaseCitation Excerpt :For both kainic acid (Arabadzisz et al., 2005a; Dugladze et al., 2007; Riban et al., 2002) and pilocarpine (Chauvière et al., 2009; Colom, 2006; Karunakaran et al., 2016; Lee et al., 2017b; Marcelin et al., 2009) models of TLE in rodents, a significant reduction of theta power follows both acutely induced status-epilepticus as well as chronic spontaneous and recurring seizures (Fig. 5). Changes in oscillatory power occur bi-laterally, in the dorsal (Arabadzisz et al., 2005a; Colom, 2006; Dugladze et al., 2007; Karunakaran et al., 2016; Lee et al., 2017b; Marcelin et al., 2009) and ventral hippocampus (Arabadzisz et al., 2005a; Dugladze et al., 2007) as well as the medial septum (Arabadzisz et al., 2005a; Colom, 2006). Theta oscillations during interictal periods within hippocampal CA3 are also slower in epileptic animals compared to controls, consistent with observations in CA1 hippocampus of kainate-treated (Inostroza et al., 2013) or pilocarpine-treated (Marcelin et al., 2009) animals.