Dysregulation of the Suprachiasmatic Nucleus Disturbs the Circadian Rhythm and Aggravates Epileptic Seizures by Inducing Hippocampal GABAergic Dysfunction in C57BL/6 Mice

Jul 26, 2024Journal of pineal research

Disrupted Brain Clock Worsens Epileptic Seizures by Affecting Inhibitory Signals in the Memory Area of Mice

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Abstract

Mice with SCN lesions exhibited increased daytime seizure frequency and diminished GABAergic efficacy.

Daytime seizures were more frequent in mice with pilocarpine-induced epilepsy and SCN lesions.
Core body temperature showed irregular oscillations in epileptic mice with SCN disturbances.
Alterations in circadian genes were observed in both the suprachiasmatic nucleus and the hippocampus.
Enhanced activation of GABAergic projections from the SCN to the hippocampus was noted in the epileptic model.
Reduced expression of the Bmal1 gene was found in patients with medial temporal lobe epilepsy, which may impact GABA receptor pathways.
Targeted deletion of Bmal1 in SCN neurons worsened seizure severity and caused hippocampal GABAergic signaling impairment.

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The interplay between circadian rhythms and epilepsy has gained increasing attention. The suprachiasmatic nucleus (SCN), which acts as the master circadian pacemaker, regulates physiological and behavioral rhythms through its complex neural networks. However, the exact role of the SCN and its Bmal1 gene in the development of epilepsy remains unclear. In this study, we utilized a lithium-pilocarpine model to induce epilepsy in mice and simulated circadian disturbances by creating lesions in the SCN and specifically knocking out the Bmal1 gene in the SCN neurons. We observed that the pilocarpine-induced epileptic mice experienced increased daytime seizure frequency, irregular oscillations in core body temperature, and circadian gene alterations in both the SCN and the hippocampus. Additionally, there was enhanced activation of GABAergic projections from the SCN to the hippocampus. Notably, SCN lesions intensified seizure activity, concomitant with hippocampal neuronal damage and GABAergic signaling impairment. Further analyses using the Gene Expression Omnibus database and gene set enrichment analysis indicated reduced Bmal1 expression in patients with medial temporal lobe epilepsy, potentially affecting GABA receptor pathways. Targeted deletion of Bmal1 in SCN neurons exacerbated seizures and pathology in epilepsy, as well as diminished hippocampal GABAergic efficacy. These results underscore the crucial role of the SCN in modulating circadian rhythms and GABAergic function in the hippocampus, aggravating the severity of seizures. This study provides significant insights into how circadian rhythm disturbances can influence neuronal dysfunction and epilepsy, highlighting the therapeutic potential of targeting SCN and the Bmal1 gene within it in epilepsy management.

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Dysregulation of the Suprachiasmatic Nucleus Disturbs the Circadian Rhythm and Aggravates Epileptic Seizures by Inducing Hippocampal GABAergic Dysfunction in C57BL/6 Mice

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