Epilepsy affects 1–2% of the general population and treatment options for this debilitating disorder are limited. Although the mechanisms that underlie seizure initiation and generation are still not fully understood, an imbalance between excitation and inhibition in the cortex is thought to be a critical factor. Fast-spiking interneurons that express the calcium-binding protein parvalbumin (parvalbumin-positive interneurons) make up the dominant inhibitory system of the neocortex and critically regulate the output of the pyramidal neurons. Two studies in this issue of Nature Neuroscience examine the mechanistic link between parvalbumin-positive interneurons and seizures and causally implicate parvalbumin-positive interneuron excitability to seizure generation in rodent models.

Neuregulin 1 (NRG1) is a neurotrophic factor that activates the kinase activity of ErbB4 receptors. Previous work had shown that ErbB4 expression is high in parvalbumin-positive interneurons and that NRG1 can regulate GABAergic transmission.

Li et al. on page 267 use transgenic mice, biochemistry, pharmacology and electrophysiology to manipulate NRG1-ErbB4 signaling and examine its effects on parvalbumin-positive interneuron excitability. They find that NRG1 and ErbB4 normally enhance parvalbumin-positive interneuron excitability by suppressing the voltage-activated potassium channel Kv1.1, altering the membrane threshold for the generation of action potentials. Although the detailed mechanism by which NRG1 affects Kv1.1 activity is not known, the authors find that NRG1 regulates the level of tyrosine phosphorylation of the Kv1.1 channel. Crucially, they find that mice lacking ErbB4 specifically in parvalbumin-positive interneurons have more severe seizures in response to convulsants. Li et al. also find that ErbB4, but not ErbB2, expression is reduced in cortical tissue excised from humans suffering from temporal lobe epilepsy.

In an independent report, Tan et al. on page 258 corroborate the critical involvement of NRG1-ErbB4 signaling in parvalbumin-positive interneurons to epilepsy. They find that, in a kindling model of epilepsy, seizure activity increases NRG1 levels. In the same time frame, the phosphorylated form of the ErbB4 receptor is also increased. Tan et al. also find that intracerebral infusion of NRG1 delays the onset of kindling, whereas specific deletion of ErbB4 in parvalbumin-positive interneurons promotes kindling progression. Notably, they generate mice in which ErbB4 is specifically ablated in CaMKIIa-positive neurons (presumed to be pyramidal cells) but observed no effect on seizures. Moreover, the authors report that NRG1-ErbB4 signaling affects the sprouting of hippocampal mossy fibers into the dentate inner layer, a pathological feature of limbic epilepsy.

Together, both studies provide powerful evidence to causally implicate the NR1-ErbB4 pathway in the regulation of parvalbumin-positive interneuron excitability and seizure generation, and also point to new targets for future anticonvulsive therapy.