Pharmacological modulation of th N-Methyl-D-Aspartate receptor response in neurons derived from induced pluripotent stem cells of individuals with Down syndrome to memantine.

Abstract

Down syndrome (DS), also known as trisomy 21 (T21), which involves the presence of an extra copy of human chromosome 21 (HSA21), is the most common autosomal aneuploidy in live births. Intellectual disability is present in 100% of individuals, many of whom continue to experience learning and memory impairments and a higher risk of developing a neuropathology indistinguishable from Azheimer's disease. The glutamatergic hypothesis, which suggests a pathogenic role for altered NMDA receptors (NMDARs), has been investigated in relation to the neuropathology of DS. This hypothesis postulates that NMDA receptors are tonically overactive in individuals with DS. The initial consequence of this dysfunction state would be the excessive calcium (Ca2+) influx through the postsynaptic membrane, increase of synaptic noise and compromised neural plasticity. The chronic persistence of this excessive influx of Ca2+ would lead to excitotoxic neuronal dysfunction and cell death, negatively impacting the cognitive abilities of individuals with DS. Preliminary and unpublished studies from our group on neurons differentiated from induced pluripotent stem cells (iPSCs) have shown altered functioning of this receptor, corroborating with studies in animal models. Therefore, this project aims to study the response of the NMDA receptor in neurons differentiated from T21-iPSCs to the non-competitive agonist memantine. The investigation of the NMDA receptor pathway and of drugs that regulate these receptors in differentiated neurons from T21-iPSCs is unprecedented, will be relevant for understanding the neuropathology of DS, and will provide an important resource for developing new therapeutic strategies.