PERINEURONAL NETS MEDIATE INTERREGIONAL COMMUNICATION AND SPATIAL MEMORY RECALL

Effective communication between the hippocampus and neocortex is critical for consolidating and retrieving episodic memories. The retrosplenial cortex (RSC) is central to this process, integrating hippocampal output with cortical networks to support spatial learning and memory. Inhibitory interneurons in the granular RSC (RSCg) regulate local circuit dynamics and long-range input, and are enwrapped by perineuronal nets (PNNs), specialised extracellular matrix structures that stabilise their activity and connectivity. However, the contribution of PNNs to interregional communication remains unclear.

Here, we examined how PNN degradation in the RSCg affects recent and remote spatial memory recall and alters neuronal activity in the RSCg and dorsal CA1 (dCA1). PNN degradation impaired memory recall in the Active Place Avoidance task regardless of whether the memory was recently or remotely acquired. In the RSCg, we observed an overall increase in cfos+ cells, alongside a higher number and proportion of cfos+ PNN+ cells, consistent with increased inhibitory drive.

Using in vivo electrophysiological recordings in awake, head-fixed mice, we found that PNN degradation disrupted gamma oscillations in the RSCg and theta oscillations in dCA1, and reduced gamma coupling between the two regions, indicating weakened interregional communication. In the RSCg, excitatory units exhibited greater spiking irregularity, lower firing rates, and weaker theta–gamma coupling. Cross-correlogram analyses further revealed a loss of coordinated spike pairs between dCA1 and RSCg, reflecting reduced functional synaptic connectivity.

These findings suggest that PNN degradation enhances inhibitory tone while diminishing gamma-mediated coupling, ultimately disrupting the precise coordination required for hippocampal–RSC communication and memory retrieval.