Perineuronal nets (PNNs), a specialized form of an extracellular matrix (ECM), surround numerous neurons in the CNS and allow synaptic connectivity through holes in its structure. We hypothesize that PNNs serve as gatekeepers that guard and protect synaptic territory and thus may stabilize an engram circuit. We present high-resolution and 3D EM images of PNN-engulfed neurons in mice brains, showing that synapses occupy the PNN holes and that invasion of other cellular components is rare. PNN constituents in mice brains are long-lived and can be eroded faster in an enriched environment, while synaptic proteins have a high turnover rate. Preventing PNN erosion by using pharmacological inhibition of PNN-modifying proteases or matrix metalloproteases 9 (MMP9) knockout mice allowed normal fear memory acquisition but diminished long-term memory stabilization, supporting the above hypothesis.

Varda Lev-Ram completed her PhD at the Weizmann Institute of Science in Rehovot, Israel, where her research integrated immunology, electrophysiology, and vital dyes optical imaging. During her postdoctoral studies, she explored the effects of cone snail toxins on nerve activity, as well as analyzed calcium transients in cerebellar Purkinje neurons and the roles of nitric oxide and cAMP in cerebellar long-term potentiation (LTP) and depression (LTD). Lev-Ram later became a Senior Project Scientist in Dr. Roger Y. Tsien’s lab at the University of California, San Diego, where her research focused on learning and memory. Specifically, she investigated the hypothesis that the pattern of holes in perineuronal nets holds the CODE for life-long memories.