Perineuronal Nets Restrict the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region

Long-term depression (LTD) of synaptic efficacy is widely regarded as a cellular basis of learning and memory. The magnitude of hippocampal CA1 LTD induced by low-frequency stimulation (LFS) declines with age, but the mechanisms involved remain poorly understood. Perineuronal nets (PNNs) are specialized extracellular matrix structures that function in dampening synaptic plasticity during postnatal development, suggesting that PNN formation may restrict LTD induction in the adult hippocampus. Here, we show that PNNs tightly enwrap a subpopulation of parvalbumin (PV) interneurons in the hippocampal CA1 region and enzymatic removal of PNNs with the chondroitinase ABC alters the excitatory/inhibitory synaptic balance toward more excitation and restores the ability of LFS to induce an N-methyl-D-aspartate receptor-dependent LTD at Schaffer collateral-CA1 synapses in slices from male adult mice. Early interference with depolarizing GABA with Na⁺-K⁺-2Cl^- cotransporter inhibitor bumetanide impairs the maturation of PNNs and enhances LTD induction. These results provide novel insights into a previously unrecognized role for PNNs around PV interneurons in restricting long-term synaptic plasticity at excitatory synapses on hippocampal CA1 neurons in adulthood.