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Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca 2ϩ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, longterm plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarizationinduced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/ kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced longterm hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo feverinduced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

Loss of cells from the hilus of the dentate gyrus is a major histological hallmark of human temporal lobe epilepsy. Hilar mossy cells, in particular, are thought to show dramatic numerical reductions in pathological conditions, and one prominent theory of epileptogenesis is based on the assumption that mossy cell loss directly results in granule cell hyperexcitability. However, whether it is the disappearance of hilar mossy cells from the dentate gyrus circuitry after various insults or the subsequent synaptic-cellular alterations (e.g., reactive axonal sprouting) that lead to dentate hyperexcitability has not been rigorously tested, because of the lack of available techniques to rapidly remove specific classes of nonprincipal cells from neuronal networks.We developed a fast, cell-specific ablation technique that allowed the targeted lesioning of either mossy cells or GABAergic interneurons in horizontal as well as axial (longitudinal) slices of the hippocampus. The results demonstrate that mossy cell deletion consistently decreased the excitability of granule cells to perforant path stimulation both within and outside of the lamella where the mossy cell ablation took place. In contrast, ablation of interneurons caused the expected increase in excitability, and control aspirations of the hilar neuropil or of interneurons in the presence of GABA receptor blockers caused no alteration in granule cell excitability.These data do not support the hypothesis that loss of mossy cells from the dentate hilus after seizures or traumatic brain injury directly results in hyperexcitability.

Recent experimental and modeling results demonstrated that surviving mossy cells in the dentate gyrus play key roles in the generation of network hyperexcitability. Here we examined if mossy cells exhibit long-term plasticity in the posttraumatic, hyperexcitable dentate gyrus. Mossy cells 1 wk after fluid percussion head injury did not show alterations in their current-firing frequency (I-F) and current-membrane voltage (I-V) relationships. In spite of the unchanged I-F and I-V curves, mossy cells showed extensive modifications in Na(+), K(+) and h-currents, indicating the coordinated nature of these opposing modifications. Computational experiments in a realistic large-scale model of the dentate gyrus demonstrated that individually, these perturbations could significantly affect network activity. Synaptic inputs also displayed systematic, opposing modifications. Miniature excitatory postsynaptic current (EPSC) amplitudes were decreased, whereas miniature inhibitory postsynaptic current (IPSC) amplitudes were increased as expected from a homeostatic response to network hyperexcitability. In addition, opposing alterations in miniature and spontaneous synaptic event frequencies and amplitudes were observed for both EPSCs and IPSCs. Despite extensive changes in synaptic inputs, cannabinoid-mediated depolarization-induced suppression of inhibition was not altered in posttraumatic mossy cells. These data demonstrate that many intrinsic and synaptic properties of mossy cells undergo highly specific, long-term alterations after traumatic brain injury. The systematic nature of such extensive and opposing alterations suggests that single-cell properties are significantly influenced by homeostatic mechanisms in hyperexcitable circuits.