Structural plasticity of the axon initial segment in hippocampal granule cells after entorhinal denervation

Entorhinal cortex lesion (ECL) results in a layer-specific denervation of dentate gyrus granule cells, depriving them of their main excitatory input. Granule cells respond to this challenge with structural and functional adaptations of their dendrites and spines. In the present study we tested whether the axon initial segment (AIS) of granule cells and its cisternal organelle (CO) participate in this adaptive response, as both can undergo structural plasticity following changes in afferent drive. To this end, we performed in vivo unilateral ECL in C57BL/6 mice, perfused them at 1, 3, 7, 14, or 28 days post-lesion, and stained their brain sections for the AIS marker βIV-spectrin and for Synaptopodin (Synpo), an essential protein and marker of the CO. AIS length and Synpo cluster number and size were evaluated in granule cells from the ipsi- and contralateral hemispheres. We found that the lesioned hemisphere reacts to denervation with a shortening of the AIS and an increase in Synpo cluster density and size at different post-lesion time points. Thus, we provide first evidence for changes occurring in the AIS and CO following entorhinal denervation, indicating that the output compartment of neurons participates in the adaptive response of neurons to denervation. • The axon initial segment (AIS) of granule cells remodels following denervation • AIS of granule cells in the lesioned hemisphere shrink in size • Synaptopodin (cisternal organelle) cluster density and size increase post-lesion • First evidence for denervation-induced changes of the output compartment of neurons • Indications that long-term network rearrangements also affect the AIS in the unlesioned hemisphere