Synaptic remodeling of entorhinal input contributes to an aberrant hippocampal network in temporal lobe epilepsy

Abstract

The hippocampus is reciprocally connectedwith the entorhinal cortex.Although several studies emphasized a role for the entorhinal cortex in mesial temporal lobe epilepsy (MTLE), it remains uncertain whether its synaptic connections with the hippocampus are altered. To address this question, we traced hippocampo-entorhinal and entorhino-hippocampal projections, assessed their connectivity with the respective target cells and examined functional alterations in a mouse model for MTLE.We show that hippocampal afferents to the dorsal entorhinal cortex are lost in the epileptic hippocampus. Conversely, entorhino-dentate projections via themedial perforant path (MPP) are preserved, but appear substantially altered on the synaptic level.Confocal imaging and 3D-reconstruction revealed that new putative contacts are established between MPP fibers and dentate granule cells (DGCs). Immunohistochemical identification of pre- and postsynaptic elements indicated that these contacts are functionally mature synapses. On the ultrastructural level, pre- and postsynaptic compartments ofMPP synapseswere strongly enlarged. The length and complexity of postsynaptic densities were also increased pointing to long-termpotentiation-relatedmorphogenesis. Finally, wholecell recordings of DGCs revealed an enhancement of evoked excitatory postsynaptic currents. In conclusion, the synaptic rearrangement of excitatory inputs to DGCs fromthemedial entorhinal cortex may contribute to the epileptogenic circuitry inMTLE.