Assessing the consequences of AMPARs defective transport in an AP4 deficiency mouse model

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Mutations in the genes coding for a protein complex named AP-4 cause a rare syndrome characterized by severe intellectual disability and progressive spastic paraplegia, known as AP-4 deficiency syndrome. The mechanism by which mutations in these genes cause such a severe neurological phenotype is unknown. Based on our preliminary experiments, our hypothesis is that the lack of AP-4 leads to defects in a class of synaptic glutamate receptors named AMPA receptors (AMPAR). These are fundamental for neuronal communication, and their proper functioning is required for synaptic plasticity. As such, we hypothesise that a reduction of AMPAR levels at synapses in AP-4 deficiency patients is likely to induce defects in cognitive functions. Our aim is to study how AMPARs are affected in neurons lacking AP-4, more specifically its component AP-4ε. To do this, we will take advantage of genetically modified mouse models that lack functional AP-4ε, and we will conduct in vitro and advanced in vivo studies to validate our hypothesis. We expect that this research will shed light on the molecular bases of AP-4 deficiency syndrome and will allow us to identify a potential target for the development of future therapies.