Pediatric Epilepsy Mechanisms: Expanding the Paradigm of Excitation/Inhibition Imbalance

Abstract

Mechanisms underlying seizures and epilepsy have traditionally been considered to involve abnormalities of ion channels or synaptic function. Those considerations gave rise to the excitation/inhibition (E/I) imbalance theory, whereby increased excitation, decreased inhibition, or both favor a hyperexcitable state and an increased propensity for seizure generation and epileptogenesis. Several recent findings warrant reconsideration and expansion of the E/I hypothesis: novel genetic mutations have been identified that do not overtly affect E/I balance; neurotransmitters may exert paradoxical effects, especially during development; anti-seizure medications do not necessarily work by decreasing excitation or increasing inhibition; and metabolic factors participate in the regulation of neuronal and network excitability. These novel conceptual and experimental advances mandate expansion of the E/I paradigm, with the expectation that new and exciting therapies will emerge from this broadened understanding of how seizures and epilepsy arise and progress.

Keywords: STXBP1; antiseizure drugs; epilepsy; excitation; genetic mutations; inhibition; ketogenic diet; levetiracetam; metabolism; seizures; synaptic function.

Figure 1

Schematic showing standard paradigm for understanding the balance between excitation (E) and inhibition (I) in the production of seizures and epilepsy. Any physiological change that increases E or decreases I (or both) will tip the balance toward excitation and possible seizure occurrence. GABA, gamma-aminobutyric acid; glut, glutamate; Na, sodium; K, potassium.

Figure 2

Selected examples of epilepsy mechanisms in which the E/I balance concept may not be immediately applicable. (A) STXBP1 is a protein essential for neurotransmitter vesicle docking and fusion to enable subsequent release of neurotransmitter. This protein binds to the soluble N-ethylmaleimide attachment receptor (SNARE) complex (see text) to allow neurotransmitter release. Mutation of the gene that encodes STXBP1 (STXBP1) impairs neurotransmitter release (both excitatory and inhibitory neurotransmitters) and leads to a syndrome of neurodevelopmental disorder and severe epilepsy. (B) Early in development, GABA is excitatory rather than inhibitory, related in part to age-specific intracellular chloride concentrations. (C) The antiseizure drug levetiracetam (LEV) binds to a synaptic vesicle protein called SV2A, leading to reduced vesicle docking and neurotransmitter release. LEV also inhibits presynaptic N-type calcium channels and release of calcium from intracellular stores. (D) Overview of glucose (Gluc) metabolism. Glucose enters the cell from the bloodstream and then undergoes glycolysis for the eventual production of ATP. Metabolic control points for potential epilepsy therapy are indicated in the boxes. STXBP1, syntaxin-binding protein 1; LGIT, low glycemic index treatment; 2DG, 2-deoxyglucose; KD, ketogenic diet; MAD, modified Atkins diet; ATP, adenosine triphosphate; TCA, tricarboxylic acid cycle; ACoA, acetyl-co-enzyme A; Lac, lactate; Pyr, pyruvate.