Zn2+ dependent regulation of ProSAP2/Shank3 levels during synaptogenesis and synapse maturation

Neuronal morphology and number of synapses is not static, but can change in response to a variety of factors, a process called synaptic plasticity. Zn2+ ions, which are highly enriched within the postsynaptic density, are able to influence the recruitment of ProSAP2/Shank3 proteins to PSDs during the course of synaptogenesis and synapse maturation in hippocampal neurons. Depletion of synaptic Zn2+ along with the knockdown of zinc-insensitive Shank1 causes the rapid disintegration of PSDs and the loss of several postsynaptic molecules including Homer1, PSD-95 and NMDA receptors. Therefore, regulating synaptic ProSAP2/Shank3 levels can be one of the major targets for drugs used as neuro-chemical therapeutics in PMS. Unfortunately, the majority of drugs is not able to cross the blood–brain barrier (BBB) and is therefore distributed within the CNS parenchyma. Therefore, we use novel biodegradable Nanoparticles (NPs), made of poly-lactide-co-glycolide (PLGA) conjugated with glycopeptides that are able to cross the BBB. A thorough characterization of NPs cell toxicity, stability, cellular uptake und cell trafficking has been performed. Moreover, NPs were loaded with Zn2+. Hippocampal neurons growing under control as well as zinc supplemented and zinc depleted conditions showed a reduction of ProSAP2/Shank3 positive signals under zinc depletion and an increase under zinc supplementation. Our results show that drug - loaded NPs might be an important tool to explore the influence of altered zinc levels on ProSAP2/Shank3 localization in PMS