Characterization of the Electrophysiological Properties of Human Pluripotent Stem Cell derived Neurons HPSC from Fragile X Syndrome Patients

Abstract

Fragile X Syndrome (FXS) is an X-linked disorder and the most common form of inherited intellectual disability and autism. It is caused by an increased CGG triplet repeat mutation in the 5 UTR of the Fragile X mental retardation 1 (FMR1) gene, thereby silencing the gene and subsequent loss of its product. Data from animal models suggest that FMRP expression is necessary for proper neuronal development and normal synaptic physiology. Clinical investigations to develop FXS specific treatments based on the above preclinical findings have limited success. newlineThus, it is imperative to look into more human-based FXS in vitro models using neural progenitor cells and compare them with the existing animal models of FXS. The neurons derived from human stem cells of patients with FXS can therefore serve as an invaluable model to study the progression of the symptoms of FXS in vitro and subsequently help in developing new therapies. In my PhD, I focused on studying the functional properties of human stem cell derived FXS neurons and rescuing the potential defects. newline newlineResults: newline Neurons lacking FMRP exhibit aberrant network activity when co-cultured with primary mouse astrocytes high frequency bursts but shorter duration than control neurons. newline Neurons lacking FMRP display reduced persistent sodium channel current (INaP) and reduced persistent big conductance calcium-activated potassium (BKCa) current. newline Human astrocytes derived from pluripotent stem cells modulate the network activity of hPSC derived cortical neurons, mediated through the astrocyte conditioned medium (ACM). newline ACM mediates these effects is through the molecule S100and#946;, which potentiates the persistent sodium channel. newline