Unit Activity of Hippocampal Interneurons before Spontaneous Seizures in an Animal Model of Temporal Lobe Epilepsy

Abstract

Mechanisms of seizure initiation are unclear. To evaluate the possible roles of inhibitory neurons, unit recordings were obtained in the dentate gyrus, CA3, CA1, and subiculum of epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Most interneurons in the dentate gyrus, CA1, and subiculum increased their firing rate before seizures, and did so with significant consistency from seizure to seizure. Identification of CA1 interneuron subtypes based on firing characteristics during theta and sharp waves suggested that a parvalbumin-positive basket cell and putative bistratified cells, but not oriens lacunosum moleculare cells, were activated preictally. Preictal changes occurred much earlier than those described by most previous in vitro studies. Preictal activation of interneurons began earliest (Ͼ4 min before seizure onset), increased most, was most prevalent in the subiculum, and was minimal in CA3. Preictal inactivation of interneurons was most common in CA1 (27% of interneurons) and included a putative ivy cell and parvalbumin-positive basket cell. Increased or decreased preictal activity correlated with whether interneurons fired faster or slower, respectively, during theta activity. Theta waves were more likely to occur before seizure onset, and increased preictal firing of subicular interneurons correlated with theta activity. Preictal changes by other hippocampal interneurons were largely independent of theta waves. Within seconds of seizure onset, many interneurons displayed a brief pause in firing and a later, longer drop that was associated with reduced action potential amplitude. These findings suggest that many interneurons inactivate during seizures, most increase their activity preictally, but some fail to do so at the critical time before seizure onset.

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

“…Previous work demonstrated that inhibitory hippocampal neurons display progressive synchrony and increased firing rates minutes before the onset of pyramidal neuron hyperexcitability and sustained ictal spiking (29,30). Thus, increased I Na,P in CA3 Scn8a N1768D/+ inhibitory neurons may be critical in the preictal transition to spontaneous seizures in mutant hippocampus.…”

Virtual Cortical Resection Reveals Push-Pull Network Control Preceding Seizure Evolution

“…They raise questions such as, “What is the neuroanatomical substrate for network nodes that drive or contain seizures?” Might there be direct anatomical dysfunction such as loss of inhibitory inter-neurons, aberrant fiber-sprouting or changes in local gap junctions or ion channel expression that correlate with desynchronizing or synchronizing functional regions? Recent work at the cellular level indicates that seizure generation is complex, involving interactions between many neuronal subtypes both within and surrounding seizure-generating regions (Toyoda et al, 2015; Truccolo et al, 2011). Studies establishing a link between macroscale network structure and microscale neuroarchitectonics have demonstrated that heterogeneity of macroscale structure, such as regions of high and low node strengths often associated with the seizure-onset zone (Khambhati et al, 2015; Rummel et al, 2013; Schevon et al, 2007; Warren et al, 2010; Zaveri et al, 2009), is related to increasing complexity in the morphological structure of pyramidal neurons, a common post-synaptic site of excitatory neural activity (Scholtens et al, 2014; van den Heuvel et al, 2015).…”

GABAergic networks jump‐start focal seizures

“…[18][19][20] These studies have shown that the initial 5-10 s of a seizure correlate with a virtual cease of principal neuron activity along with interneuron firing Intracerebral signals recorded with multichannel stereo-EEG recording electrodes in a patient with a right frontal cortical dysplasia during presurgical monitoring. The onset of the seizure (arrows) correlates with low-voltage fast activity in the epileptogenic zone (contacts A3, B3, B4, C4, C5, C6, and D3 recorded with multichannel depth electrodes).…”