Genetic and pharmacological rescue of TM4SF2 loss of function in animal model and iPS cells

Intellectual disability (ID) affects 2–3% of the world’s population and typically begins during childhood, causing impairments in social skills and cognitive abilities. Mutations in the TM4SF2 gene, which encodes the TSPAN7 protein, cause a severe form of intellectual disability, and currently, no therapy is able to ameliorate this cognitive impairment. We found that TSPAN7 regulates AMPA Receptor (AMPAR) trafficking by inhibiting PICK1-GluA2 interaction. We also found that loss of TM4SF2 in mice compromises AMPARs currents and that AMPARs positive modulator restored the normal synaptic transmission. With this project, using genetic and pharmacological approaches in combination with molecular biology and behavioural studies, we aim to revert neurological phenotype caused by TM4SF2 mutations. For this purpose, we will attempt to revert the synaptic alterations of TM4SF2-/y mice by generating TM4SF2-/y/PICK1+/-mice (aim 1) and by pharmacological therapies (aim 2). Furthermore, we will study neurons obtained from patients-derived hiPSCs and their isogenic controls (corrected for TM4SF2 mutations) for altered AMPAR function and evaluate the ability of AMPARs modulators to rescue synaptic alterations. This study will elucidate the role of AMPARs in ID caused by TM4SF2 mutations and investigate the role of AMPARs modulation as a therapy.