Abstract
•Initiation of pathological synchronous events such as epileptic spikes and seizures is linked to the hyperexcitability of the neuronal network in both humans and animals. •In the present study, we show that epileptiform interictal-like spikes and seizures emerged in human neocortical slices by blocking GABAA receptors, following the disappearance of the spontaneously occurring synchronous population activity. •Large variability of temporally and spatially simple and complex spikes was generated by tissue from epileptic patients, whereas only simple events appeared in samples from non-epileptic patients. •Physiological population activity was associated with a moderate level of principal cell and interneuron firing, with a slight dominance of excitatory neuronal activity, whereas epileptiform events were mainly initiated by the synchronous and intense discharge of inhibitory cells. •These results help us to understand the role of excitatory and inhibitory neurons in synchrony-generating mechanisms, in both epileptic and non-epileptic conditions. Understanding the role of different neuron types in synchrony generation is crucial for developing new therapies aiming to prevent hypersynchronous events such as epileptic seizures. Paroxysmal activity was linked to hyperexcitability and to bursting behaviour of pyramidal cells in animals. Human data suggested a leading role of either principal cells or interneurons, depending on the seizure morphology. In the present study, we aimed to uncover the role of excitatory and inhibitory processes in synchrony generation by analysing the activity of clustered single neurons during physiological and epileptiform synchronies in human neocortical slices. Spontaneous population activity was detected with a 24-channel laminar microelectrode in tissue derived from patients with or without preoperative clinical manifestations of epilepsy. This population activity disappeared by blocking GABAA receptors, and several variations of spatially and temporally simple or complex interictal-like spikes emerged in epileptic tissue, whereas peritumoural slices generated only simple spikes. Around one-half of the clustered neurons participated with an elevated firing rate in physiological synchronies with a slight dominance of excitatory cells. By contrast, more than 90% of the neurons contributed to interictal-like spikes and seizures, and an intense and synchronous discharge of inhibitory neurons was associated with the start of these events. Intrinsically bursting principal cells fired later than other neurons. Our data suggest that a balanced excitation and inhibition characterized physiological synchronies, whereas disinhibition-induced epileptiform events were initiated mainly by non-synaptically synchronized inhibitory neurons. Our results further highlight the differences between humans and animal models, and between in vivo and (pharmacologically manipulated) in vitro conditions.
Highlights
Understanding the role of different neuron types in the generation of physiological and pathological synchronies is crucial to identify what makes a brain region predisposed to generate hypersynchronous events, such as epileptic seizures and interictal spikes
Cell firing during spontaneous population activity (SPA) and BIC-induced events We examined the discharge of neurons relative to the local field potential gradient (LFPg) peak of the SPA, interictal-like spikes (IISs) and seizure events with two approaches
Patient groups Patients were distributed into four groups by experienced neurologists (Table 1, (Tóth et al, 2018): 1) patients with pharmacoresistant epilepsy, 2) patients with generalized or focal tonic-clonic seizures who were seizure free with appropriate medication, 3) patients with one generalized tonicclonic seizure or with occasional seizures, and with no need for medication
Summary
Understanding the role of different neuron types in the generation of physiological and pathological synchronies is crucial to identify what makes a brain region predisposed to generate hypersynchronous events, such as epileptic seizures and interictal spikes. Knowledge about the cellular and network mechanisms related to synchrony generation mainly derive from the hippocampus and the surrounding medial temporal areas, while the role of different neuron types in synchronisation processes of other neocortical regions remains mainly uncovered. We induced epileptic seizures and interictal spikes with the GABAA receptor antagonist bicuculline (BIC) in human neocortical slices derived from epileptic and tumour patients and compared these pathological events to synchronous population activity spontaneously occurring in physiological solution. We aimed to get insight into the cellular mechanisms by analysing the discharge properties of clustered excitatory and inhibitory neurons during both epileptiform and physiological synchronous events
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