Abstract
Structural, functional, and molecular reorganization of denervated neural networks is often observed in neurological conditions. The loss of input is accompanied by homeostatic synaptic adaptations, which can affect the reorganization process. A major challenge of denervation-induced homeostatic plasticity operating in complex neural networks is the specialization of neuronal inputs. It remains unclear whether neurons respond similarly to the loss of distinct inputs. Here, we used in vitro entorhinal cortex lesion (ECL) and Schaffer collateral lesion (SCL) in mouse organotypic entorhino-hippocampal tissue cultures to study denervation-induced plasticity of CA1 pyramidal neurons. We observed microglia accumulation, presynaptic bouton degeneration, and a reduction in dendritic spine numbers in the denervated layers 3 days after SCL and ECL. Transcriptome analysis of the CA1 region revealed complex changes in differential gene expression following SCL and ECL compared to non-lesioned controls with a specific enrichment of differentially expressed synapse-related genes observed after ECL. Consistent with this finding, denervation-induced homeostatic plasticity of excitatory synapses was observed 3 days after ECL but not after SCL. Chemogenetic silencing of the EC but not CA3 confirmed the pathway-specific induction of homeostatic synaptic plasticity in CA1. Additionally, increased RNA oxidation was observed after SCL and ECL. These results reveal important commonalities and differences between distinct pathway lesions and demonstrate a pathway-specific induction of denervation-induced homeostatic synaptic plasticity.