According to a study published in the Journal of Neuroscience, changes to extrasynaptic GABA (γ-aminobutyric acid) receptors in a mouse model of epilepsy could contribute to overall changes in neural excitability.

Peng et al. studied the expression of specific GABA receptor subunits in mice in which epilepsy had been induced by treatment with pilocarpine. GABA receptors that contain the δ-subunit are usually found outside synapses, where they might be tonically active or activated by transmitter spillover from nearby synapses. These extrasynaptic GABA receptors are thought to be important for controlling neuronal excitability, and mutations in the gene for the δ-subunit have been identified in patients with generalized epilepsy.

In the mouse model of epilepsy that was used for this study, a single treatment with pilocarpine is used to induce a chronic epileptic condition with spontaneous seizures. The authors monitored changes in the expression of the δ-subunit over the period after the injection. After four days, diffuse immunohistochemical labelling for the δ-subunit was decreased in the molecular layer of the dentate gyrus, but after a week this general decrease in labelling was accompanied by a specific increase in the labelling of interneurons (most of which are inhibitory). These changes were sustained over the 60 days of the study.

If excitatory neurons in the dentate gyrus have fewer extrasynaptic GABA receptors, and inhibitory interneurons in the same area have more, this could lead to a decrease in overall inhibition in this area and an increase in the excitability of the neuronal network. To test this, the authors performed electrophysiology on brain slices from the pilocarpine-treated mice. As predicted, these slices were more excitable than those from control mice, and they were also resistant to the normal decrease in excitability caused by treatment with a neurosteroid.

These findings point to the potential importance of extrasynaptic GABA receptors in epilepsy, and show that differential changes in receptor expression in interneurons and principal neurons might produce a combined effect on excitability in models of epilepsy.