Reichelt_2026_Neuropsychopharmacology_51_1245

Alterations to perineuronal nets (PNNs) are linked to cognitive deficits observed in multiple neuropsychiatric and neurodegenerative conditions. PNNs are proposed both to limit neuronal plasticity and to protect neuronal populations critical for cognitive function. Here, we assessed these two distinct proposed functions of PNNs in the same experimental procedure, varying only the timing of PNN manipulation. Enzymatic degradation of hippocampal PNNs 4 weeks after an obesogenic high-fat high-sugar (HFHS) diet - which causes hippocampal-dependent memory impairments - restored memory performance, demonstrating a key role of PNNs in plasticity. In contrast, degradation of hippocampal PNNs prior to HFHS diet exacerbated memory deficits, demonstrating PNNs' role in neuroprotection. Because PNNs primarily surround PV(+) neurons (PVNs), we hypothesized that the mechanism underlying these effects of PNN degradation would involve, at least in part, alterations in hippocampal PVN function. Thus, to see whether PNN degradation alters the function of hippocampal PVNs, we took fiber photometry measurements across multi-day timescales and found that hippocampal PNN degradation alters calcium events in PVNs. We then went on to explicitly manipulate PVNs and found that chemogenetic inhibition of hippocampal PVNs in mice on a standard diet impaired memory performance, and activation of hippocampal PVNs in mice on a HFHS diet restored memory performance, bidirectional effects that mirror the bidirectional effects of PNN degradation. Taken together, these findings support the dual plasticity and protection hypothesis of PNN function, provide evidence that key mechanisms of memory involve the interaction of PNNs and PVNs, and point to PNNs as a potential therapeutic target in cognitive decline.