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Inhibitory Neurons Cut a New Path in Epilepsy Development

Commentary Simplistically, an excitatory–inhibitory imbalance in key brain areas supports an increased propensity for seizure generation. From a structural reorganization viewpoint, that concept translates to a loss of inhibition due to cell loss and altered responses to GABA, accompanied by an increase in excitation mediated by axon sprouting and synaptic reorganization among principal neurons. Excitatory axon sprouting and synaptic reorganization (exemplified by mossy fiber sprouting in the dentate gyrus) have been widely reported in animal models of acquired temporal lobe epilepsy (TLE) and in TLE patients. Concurrently, altered GABAergic inhibition and loss of select groups of GABAergic neurons in the hippocampal formation is also associated with epilepsy development. Reorganization of inhibitory synaptic circuits in epilepsy, however, has been less well characterized than for excitatory connections. Somatostatin-immunoreactive (SOM) GABAergic interneurons in the hilus represent one group of inhibitory interneurons that is particularly vulnerable to cell death associated with induction of TLE. These neurons normally innervate the distal dendrites of dentate gyrus granule cells, providing important recurrent inhibition. The loss of a significant portion of this critical class of cells during epileptogenesis may contribute to reduced seizure threshold. However, afferent synaptic drive to surviving hilar SOM neurons is reorganized and increased in animal models of TLE (1, 2), and the axons of hilar SOM neurons sprout and form new connections with granule cells, possibly reestablishing a portion of the normal inhibitory circuitry (3). After noting that SOM immunolabeling in the dentate gyrus increased progressively after pilocarpine treatment, status epilepticus, and accompanying loss of SOM neurons in the hilus, Peng and colleagues investigated axon reorganization of SOM neurons originating in CA1 stratum oriens and found that their axons arborized aberrantly in the molecular layer of the dentate gyrus. These neurons are relatively spared in epilepsy development, and their axons do not normally invade the dentate gyrus. Using sophisticated labeling methods targeted to the stratum oriens in SOM-Cre transgenic mice, axon terminals of stratum oriens SOM neurons in pilocarpine-treated, but not control mice, were found to form symmetric (inhibitory) synaptic contacts with granule cell dendrites and dendritic spines. Normally, hilar SOM neurons make synapses on granule cell dendrites, near terminations of excitatory perforant path axons. The hilar SOM neurons are depleted in this model, but newly formed synapses from stratum oriens SOM neurons were often located near asymmetrical (excitatory) synapses on A Reorganized GABAergic Circuit in a Model of Epilepsy: Evidence from Optogenetic Labeling and Stimulation of Somatostatin Interneurons.