Denervation of brain regions is a common aspect of neurological diseases caused by traumatic brain injury or demyelination. Nevertheless, the mechanisms underlying lesion-induced reorganization of the affected brain regions is a matter of ongoing investigation.Using an entorhinal cortex lesion in mouse organotypic entorhino-hippocampal tissue cultures, we investigated denervation-induced adaptations in dentate granule cells, CA3 pyramidal neurons and their monosynaptic connection – the mossy fiber synapse. For functional and structural analysis of these cells, we employed single and paired whole-cell patch-clamp recordings as well as electron microscopy. To further elucidate the role of the spine apparatus organelle in lesion-induced plasticity, we additionally performed synaptopodin-co-immunoprecipitation and subsequent transcriptome analysis.The entorhinal cortex lesion caused a significant strengthening of excitatory neurotransmission in the investigated principle neurons and specifically at mossy fiber synapses. Apart from functional changes, ultrastructural as well as molecular adjustments were present after lesion. These plastic alterations were dependent on the presence of the spine apparatus organelle – a postsynaptic organelle that seems to be associated with ribosomes and synapse-specific mRNAs. Our results demonstrate a close relation between the spine apparatus organelle, ribosomes and local protein synthesis, which seems to be essential for the denervation-induced adjustments at hippocampal neurons.Supported by Else-Kröner Fresenius Stiftung (EKFS).