Excitatory Dentate Granule Cells Normally Contain GAD and GABA, but Does that Make Them GABAergic, and Do Seizures Shift Granule Cell Function in the Inhibitory Direction?

Few subjects in the field of epilepsy research are more actively discussed than the possible defects and disturbances in the γ-aminobutyric acid (GABA) system that might cause epilepsy. The early finding that baby food deficient in vitamin B6 (a cofactor of the GABA-synthesizing enzyme GAD) caused vitamin-reversible seizures provided one of the first clues that seizures might be caused by reduced synthesis of GABA 1, 2. Accordingly, GABA neurons have been alternately proposed to be highly vulnerable or relatively invulnerable after insults known to cause epilepsy 3, 4, and GABA-mediated inhibition is reportedly decreased, increased, lost and recovered, or none of these, in a variety of constantly compared but greatly dissimilar animal models 5. A number of recent articles focused on the seemingly paradoxic idea that the glutamatergic granule cells of the hippocampal dentate gyrus, which are possibly the most lethally excitatory cells in the brain, also may be GABAergic and may shift their functional state in the inhibitory direction after seizures occur 6. If GABA neurons are defined as cells normally expressing GAD and GABA, then granule cells are clearly GABA neurons, but what does that mean when everyone knows that granule cells are excitatory 7? Before diving into the reductionist world of experimental minutiae in which an endless number of possible mechanisms can be argued endlessly, and in which a broad perspective is the first casualty, it may be worthwhile to consider the “big picture.”