GABAergic interneurons facilitate mossy fiber excitability in the developing hippocampus.

Profound activity-dependent synaptic facilitation at hippocampal mossy fiber synapses is a unique and functionally important property. Although presynaptic ionotropic receptors, such as kainate receptors, contribute partially to the facilitation in the hippocampus, the precise mechanisms of presynaptic regulation by endogenous neurotransmitters remain unclear. In this study, we report that axonal GABA(A) receptors on mossy fibers are involved in the activity-dependent facilitation during development. In immature mouse hippocampal slices, short-train stimulation (five pulses at 25 Hz) caused frequency-dependent facilitation of not only postsynaptic responses but also presynaptic fiber volleys that represent presynaptic activities. This fiber volley facilitation was inhibited by selective GABA(A) receptor antagonists, or by enkephalin that selectively suppresses excitability of interneurons. Furthermore, we directly demonstrated that this facilitation resulted from depolarization of mossy fibers in imaging experiments using a voltage-sensitive dye. This increased mossy fiber excitability caused by depolarizing action of GABA gradually decreased with development and eventually disappeared at around postnatal day 30. These results suggested that GABA released from interneurons acted on axonal GABA(A) receptors on mossy fibers and contributed at least partially to the activity- and age-dependent facilitation in the hippocampus.