The fourth partner in synaptic functions: the development of treatment for memory enhancement through modulation of perineuronal nets

Perineuronal nets (PNNs) are increasingly recognised as critical regulators of synaptic function and information processing in the central nervous system. PNNs are specialised extracellular matrix structures that enwrap subsets of neurons and dynamically influence neuronal connectivity and plasticity. A major structural component of PNNs is the chondroitin sulfate glycosaminoglycan chain, whose sulphation pattern determines many of the biological properties of the matrix.

Our studies have demonstrated that PNNs play a pivotal role in regulating neuroplasticity across the lifespan, influencing both memory formation and cognitive flexibility. By modifying the assembly or composition of PNNs, we have shown that age-related declines in synaptic plasticity and memory can be reversed, highlighting PNNs as a promising therapeutic target for cognitive enhancement.

I shall discuss the emerging concept of PNNs as the “fourth partner” in synaptic function, complementing the presynaptic neuron, postsynaptic neuron, and glial elements of the tripartite synapse. It will also cover our recent development of small-molecule modulators of PNNs, offering a novel therapeutic strategy for memory impairment associated with ageing and neuropsychiatric disorders.