Circadian-Like Rhythmicity of Extracellular Brain Glutamate in Epilepsy

Abstract

Seizures often exhibit striking circadian-like (∼24-h) rhythms. While chronotherapy has shown promise in treating epilepsy, it is not widely used, in part because the patterns of seizure rhythmicity vary considerably among patients and types of epilepsy. A better understanding of the mechanisms underlying rhythmicity in epilepsy could be expected to result in more effective approaches which can be tailored to each individual patient. The excitatory neurotransmitter glutamate is an essential modulator of circadian rhythms, and changes in the extracellular levels of glutamate likely affect the threshold to seizures. We used a reverse translational rodent model of mesial temporal lobe epilepsy (MTLE) combined with long-term intracerebral microdialysis to monitor the hourly concentrations of glutamate in the seizure onset area (epileptogenic hippocampus) over several days. We observed significant 24-h oscillations of extracellular glutamate in the epileptogenic hippocampus (n = 4, JTK_CYCLE test, p < 0.05), but not in the hippocampus of control animals (n = 4). To our knowledge, circadian glutamate oscillations have not been observed in a seizure onset region, and we speculate that the oscillations contribute to the rhythmicity of seizures in MTLE.

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“…For example, there are many changes in brain function associated with the sleep/wake cycle and there can also be rhythmicity in different diseases. For example, some epileptic patients show marked periodicity in seizures 148,149 which may impact the optimal timing for anti-epileptic drugs. There are also circadian effects on occurrence, injury severity and recovery in stroke 150 including effects on the systemic and brain immune response.…”

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“…Decreased GABAergic neurotransmission at a given time during the day in an epileptogenic network may increase interictal activity (but also increase seizure probability). Following the same idea, a microdialysis study reveals a circadian rhythmicity of extracellular glutamate levels in experimental epilepsy 96 . In the latter study, variations of glutamate in control animals were blunted, highlighting that the circadian "rules" are altered in epilepsy.…”

The broad-spectrum activity of perampanel: state of the art and future perspective of AMPA antagonism beyond epilepsy

“…Indeed, both seizures and spikes induce LTP (172-176), which may compete with LTP occurring during everyday learning (177-179). Moreover, extracellular glutamate concentration was found to be higher during the dark period of the 24-h cycle in the hippocampus of both an MTLE translational animal model and control animals (180). However, glutamate levels had significant 24-h oscillations in epileptic hippocampi but not controls, possibly reflecting the circadian rhythmicity of temporal lobe epilepsies (180)(181)(182).…”

“…Moreover, extracellular glutamate concentration was found to be higher during the dark period of the 24-h cycle in the hippocampus of both an MTLE translational animal model and control animals (180). However, glutamate levels had significant 24-h oscillations in epileptic hippocampi but not controls, possibly reflecting the circadian rhythmicity of temporal lobe epilepsies (180)(181)(182). Therefore, AMPAR antagonists may be useful in controlling glutamate's circadian activity and inhibiting the dysfunctional LTP phenomenon, allowing the brain to learn an epileptogenic mechanism.…”