Footshock drives remodeling of perineuronal nets in retrosplenial cortex during contextual fear memory formation

•In most cortical areas Perineuronal nets (PNN) enwrap mainly GABAergic neurons, modulating synaptic plasticity.•Contextual fear conditioning (CFC) causes PNN expansion in some sensorial cortices.•After CFC the PNN in RSC remains expanded.•In the retrosplenial cortex (RSC), the footshock alone evoked a significant expansion of PNN.•Expansion of PNN in RSC was not associated with c-Fos expression in RSC. The retrosplenial cortex (RSC) plays a critical role in complex cognitive functions such as contextual fear memory formation and consolidation. Perineuronal nets (PNNs) are specialized structures of the extracellular matrix that modulate synaptic plasticity by enwrapping the soma, proximal neurites and synapsis mainly on fast spiking inhibitory GABAergic interneurons that express parvalbumin (PV). PNNs change after contextual fear conditioning (CFC) in amygdala or hippocampus, yet it is unknown if similar remodeling takes place at RSC. Here, we used Wisteria floribunda agglutinin (WFA), a ubiquitous marker of PNNs, to study the remodeling of PNNs in RSC during the acquisition or retrieval of contextual fear conditioning (CFC). Adult male mice were exposed to paired presentations of a context and footshock, or to either of these stimuli alone (control groups). The mere exposure of animals to the footshock, either alone or paired with the context, evoked a significant expansion of PNNs, both in the number of WFA positive neurons and in the area occupied by WFA staining, across the entire RSC. This was not associated with c-Fos expression in RSC nor correlated with c-Fos expression in individual PNNs-expressing neurons in RSC, suggesting that PNNs remodeling is triggered by inputs external to the RSC. We also found that PNNs remodeling was independent of the level of PV expression. Notably, PNNs in RSC remained expanded long-after CFC. These results suggest that, in male mice, the threatening experience is the main cause of PNNs remodeling in the RSC.