Interneuron Loss as a Cause of Seizures: Lessons from Interneuron-Deficient Mice

Throughout our nervous system, excitation and inhibition are exquisitely balanced to enable a multitude of functions. When this balance is disrupted, neurons experience a surplus or a deficit in excitation, either of which can have devastating consequences. In the cortex, excitation and inhibition are mediated by glutamatergic pyramidal cells and GABAergic interneurons, respectively. The loss of GABAergic inhibition in the epileptic brain places neurons in a hyperexcitable state in which they are vulnerable to the high-frequency firing that defines seizures. The association between seizures and a loss of GABAergic transmission is supported by numerous investigations of epileptic patients and animal models of epilepsy(1–3). For example, brain tissue from patients suffering from mesial temporal lobe epilepsy (MTLE), one of the most common medically intractable forms, is distinguished by a loss of specific subtypes of interneurons. Furthermore, electrophysiological studies have demonstrated that dentate gyrus granule cells from epileptic patients exhibit a functional reduction in inhibitory synaptic transmission (4). These clinical findings are consistent with extensive work in pharmacologically induced animal models of epilepsy, including models of TLE and cortical dysplasia (5–9). Although clinical and animal studies show a correlation between reduced inhibition and epilepsy, interneuron-deficient transgenic mice that exhibit an epileptic phenotype have recently confirmed that this link is causal. As such, interneuron-deficient transgenic mice can serve as mouse models of epilepsy and have the potential to significantly advance our understanding of interneuron development, interneuron function, and the importance of GABAergic inhibition in preventing seizure activity. In this chapter, we will review information that is directly relevant to our understanding of GABAergic interneuron-deficient mice, including interneuron origins and diversity, the characteristics of various types of interneuron-deficient mice, what we have learned from these mice, and the clinical applications of such mice in the treatment of epilepsy.