Figure 8.

Hypothetical schematic representation of the dentate gyrus (DG) environment in TLE rats and the levetiracetam (LEV) mechanism of action. (a) As a consequence of the death of mossy cells (yellow dotted), GABAergic cells (green dotted), and pyramidal CA3 cells (not shown), the granule cells (blue cell) remains without postsynaptic targets; their axons then “sprout” and innervate the dendrites of other granule cells (not shown) and themselves, generating the mossy fiber sprouting (MFS) and inducing granule cell hyperexcitability [1,43]. The clear augment of the population spike (PS) amplitude and the significant reduction in the onset- and peak-PS latencies in the basal excitatory transmission of TLE rats supports this phenomenon. (b) The hyperexcitability of granule cells in TLE could over-activate the surviving GABAergic interneurons (right green), increasing local inhibition. In addition, the loss of interneurons (left green dotted) provokes aberrant connections between the axons of granule cells and remaining GABAergic interneurons, which, in turn, may develop new dendritic spines and, thus, new synaptic contacts [48,51,52]. All this together would promote a hyperinhibitory environment; this could explain the changes in the short and long-term synaptic plasticity in TLE rats, such as strong depression (PPD) and the absence of facilitation (PPF) by paired pulses, and the decrease in PS long-term potentiation (PS-LTP). (c) The partial recovery of PS amplitude in basal excitatory transmission and the decrease in excitatory postsynaptic potential (EPSP)-LTP slope by LEV, could be associated with the potentiation of the GABAergic signaling through the increase in the release of γ-aminobutyric acid (GABA), suggesting that LEV may act as an effective antiseizure agent that suppresses the firing of glutamatergic neurons in the DG. OML: outer molecular layer; MML: middle molecular layer; IML: inner molecular layer; GCL: granule cell layer; pp: perforant pathway (red axon).