A review of cell-type specific circuit mechanisms underlying epilepsy

Abstract

Epilepsy is a prevalent neurological disorder, yet its underlying mechanisms remain incompletely understood. Accumulated studies have indicated that epilepsy is characterized by abnormal neural circuits. Understanding the circuit mechanisms is crucial for comprehending the pathogenesis of epilepsy. With advances in tracing and modulating tools for neural circuits, some epileptic circuits have been uncovered. This comprehensive review focuses on the circuit mechanisms underlying epilepsy in various neuronal subtypes, elucidating their distinct roles. Epileptic seizures are primarily characterized by the hyperactivity of glutamatergic neurons and inhibition of GABAergic neurons. However, specific activated GABAergic neurons and suppressed glutamatergic neurons exacerbate epilepsy through preferentially regulating the activity of GABAergic neurons within epileptic circuits. Distinct subtypes of GABAergic neurons contribute differently to epileptic activities, potentially due to their diverse connection patterns. Moreover, identical GABAergic neurons may assume distinct roles in different stages of epilepsy. Both GABAergic neurons and glutamatergic neurons with long-range projecting fibers innervate multiple nuclei; nevertheless, not all of these circuits contribute to epileptic activities. Epileptic circuits originating from the same nuclei may display diverse contributions to epileptic activities, and certain glutamatergic circuits from the same nuclei may even exert opposing effects on epilepsy. Neuromodulatory neurons, including cholinergic, serotonergic, dopaminergic, and noradrenergic neurons, are also implicated in epilepsy, although the underlying circuit mechanisms remain poorly understood. These studies suggest that epileptic nuclei establish intricate connections through cell-type-specific circuits and play pivotal roles in epilepsy. However, there are still limitations in knowledge and methods, and further understanding of epileptic circuits is crucial, particularly in the context of refractory epilepsy.

Keywords: Cell-type specific; Circuit mechanisms; Epilepsy; Neuromodulatory.

Fig. 1

GABAergic circuits in epilepsy. a The uncovered GABAergic epileptic circuits in the whole brain. The green arrows and dots represent GABAergic circuits, whose activation inhibits epileptic activity or exacerbates epileptic seizures upon inhibition, while the magenta arrows and dots exhibit the opposite effect. The dotted lines represent circuits with no significant effect on epileptic activity. b The connection patterns among different GABAergic neurons and pyramidal neurons in the cortex

Fig. 2

The uncovered glutamatergic epileptic circuits in the whole brain. The magenta arrows and dots represent glutamatergic circuits, whose activation exacerbates epileptic seizures or inhibits epileptic activity upon inhibition, while the green arrows and dots exhibit the opposite effect. The dotted lines represent circuits with no significant effect on epileptic activity

Fig. 3

The whole-brain projection of different neuromodulatory neurons. a The whole-brain projection of cholinergic neurons in the BF, PPN, and LDT. b The whole-brain projection of DA neurons in the VTA. c The whole-brain projection of 5-HT neurons in the DR. d The whole-brain projection of NE neurons in the LC. Abbreviation: Ctx cortex; CPu caudate putamen; BF basal forebrain; Th thalamus; SC superior colliculus; DR dorsal raphe nucleus; LDT laterodorsal tegmental nucleus; PPN pedunculopontine nucleus; LC locus ceruleus; VTA ventral tegmental area; SN substantia nigra; CEA central amygdala