The GAD‐given Right of Dentate Gyrus Granule Cells to Become GABAergic

The clear challenge for understanding granule cell function in health and epilepsy is to resolve the release of the transmitter at the synaptic endings, the big mossy boutons that synapse onto CA3 pyramidal cells and their filopodial extensions that form the presynaptic part of synapses onto interneurons. Granule cells in young, but not adult 11, rats and in adult guinea pigs seem to release GABA that apparently finds its way to GABAA receptors of CA3 pyramidal cells 12. The inhibitory postsynaptic current (IPSC) has a slow rise time, indicating that the receptors might be somewhat removed from the release site, but there is little doubt about the inhibitory nature of the responses in CA3 pyramidal cells 12. To complicate things further, seizures or repetitive stimulation of the perforant path seems to increase the GABAergic phenotype of granule cells both in biochemical studies 13, 14, 15, 16 and in physiological experiments 11, 17, 18. All the necessary enzymes for GABA synthesis seem to be in place 13, 14, 16, and the vesicular GABA transporter required for packaging GABA into synaptic vesicles also is present 19. The following, with all the possible permutations, are potential consequences of GABA synthesis or release from the granule cell terminals. To produce fast GABAA receptor–mediated inhibitory events in target cells. These cells include interneurons, CA3 pyramidal cells, mossy cells, and, subsequent to the epilepsy-related mossy fiber sprouting, other granule cells. To induce slow GABAB receptor–mediated inhibitory events in the target neurons mentioned earlier. To cause presynaptic inhibition through GABAB receptors of glutamate or GABA release from other neighboring terminals, or from the same terminal that just released the GABA 20. To elevate ambient levels of GABA producing tonic GABA conductances in hippocampal neurons equipped with nondesensitizing high-affinity GABAA receptors 21, 22. To buffer pH changes inside the granule cells, akin to the role of GABA in plants 23. It would be foolish to attempt to speculate on the outcome of all of these possibilities and their interactions. Much of what we want to make of the role of GABA in dentate gyrus granule cells depends on what we believe to be the function of these neurons. They have been described as being the guardians of the hippocampus against an overpowering entorhinal input 24 or as merciless excitotoxic killers of various other cell types 25. Furthermore, the outcome of inhibiting interneurons by the GABA released from phenotypically altered granule cells must be considered. Preliminary findings, after kindling-like repetitive stimulations in slices, point to the existence of granule cell–mediated synaptic GABA responses not only in CA3 pyramidal cells but also in interneurons 11. This disinhibitory alternative must be seriously considered, particularly if we accept that the role of a dentate granule cell is to communicate with a handful of CA3 pyramidal cells while silencing most others. Neuroanatomists tell us that a single granule cell makes synaptic contacts with at least an order of magnitude more interneurons than do the 15 or so CA3 pyramidal cells it innervates 26. Without any detailed experimental evidence, it will take a long time to decide whether the GABAergic phenotype of granule cells is pro- or antiepileptogenic. Nevertheless, by simultaneously releasing fast excitatory and inhibitory transmitters at times of neuronal conflagration, as in epilepsy, granule cells have revealed their ultimate Janus faces. In ancient Rome, of the many temples dedicated to Janus, one was called Ianus Geminus. It was a double-gated temple built in the Forum, serving a symbolic function. When its gates were closed, showing only one face, it signified peace within the Roman Empire. When the gates were open, both faces showing, it meant war. Alternatively, if the second face of Janus really looks into the past, the presence of GABA in granule cells during epilepsy may just be the reactivation of a developmental program reminding us of their GAD-given right to be GABAergic.