Synaptopodin-associated ribosomal hubs regulate lesion-induced homeostatic plasticity at hippocampal mossy fiber synapses

Neurological diseases can lead to the denervation of brain regions caused by demyelination, traumatic injury or cell death. Nevertheless, the molecular and structural mechanisms underlying the lesion-induced reorganization of denervated brain regions are a matter of ongoing investigation. In order to address this issue, we performed an entorhinal cortex lesion (ECL) in organotypic entorhinal-hippocampal tissue cultures and studied denervation-induced homeostatic plasticity of mossy fiber synapses, which connect dentate granule cells with CA3 pyramidal neurons and play important roles in spatial learning. Partial denervation caused a homeostatic strengthening of excitatory neurotransmission in dentate granule cells (GC), in CA3 pyramidal neurons, and their direct synaptic connections as revealed by paired recordings (GC-to-CA3). These functional changes were accompanied by ultrastructural reorganization of mossy fiber synapses, which regularly contain the plasticity-related protein synaptopodin and the spine apparatus organelle. We demonstrate that the spine apparatus organelle and its associated protein synaptopodin assemble ribosomes in close proximity to synaptic sites and moreover we unravel synaptopodin-related transcriptome, which can be linked to the expression of homeostatic synaptic plasticity. Notably, synaptopodin-deficient tissue preparations that lack the spine apparatus organelle, failed to express homeostatic adjustments of both excitatory neurotransmission and the region-specific transcriptome. Hence, synaptopodin and the spine apparatus organelle form local protein synthesis hubs that are essential for mediating lesion-induced homeostatic synaptic plasticity.