The molecular assembly of perineuronal nets by super-resolution microscopy in ageing brains.

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Perineuronal nets (PNNs) are specialised extracellular matrix structures that encase specific neuron populations within the central nervous system. PNN maturation coincides with critical period closure, where we observe a significant decrease in plasticity. Current research implicates PNNs in the control of synaptic plasticity via three main mechanisms: a) creating a physical barrier to guide axon termination, b) harbouring inhibitory molecules of axon sprouting, and c) limiting receptor motility at the synapse. Hence, we believe that manipulation of PNNs may provide a novel target for plasticity manipulation in neurodegenerative diseases, like Alzheimer's Disease. Enzymatic degradation of PNNs has already been shown to retrieve juvenile levels of plasticity in animal models, however we still face challenges with target specificity, delivery, and stability of these treatments. Furthermore, we must further interrogate the mechanisms of PNN molecular assembly and the relationship of PNN molecules to the synapse in situ, in order to understand how we can manipulate PNNs for therapeutic use. Through the use of super-resolution expansion microscopy, we aim to identify the spatial relationship of PNN molecules and synapses at 15 nm resolution. We will overcome the diffraction limit of conventional optical microscopy by embedding cultured primary PNN neurons in a hydrogel, that will undergo isotropic expansion, thereby allowing us to visualise PNN structures at the molecular level. In combination with further biophysical and dynamic analysis of PNNs we aim to discover the mechanisms of molecular assembly of PNNs on the surface of neurons.