Grant: Project Grant

Almost 100 million people worldwide or 1-2 % of the global population have been estimated to be affected by intellectual disability (ID). ID is a condition that is often first detected during early childhood and is characterized by significant challenges in both intellectual functioning, such as learning, reasoning and problem solving, as well as adaptive behaviors, such as language, literacy and social skills. ID is also associated with other neurological deficits including autism, seizures, attention deficit, cerebral palsy, vision and hearing deficiencies. Despite this level of understanding, there is still no cure or effective clinical treatment for ID. Emerging evidence, however, increasingly identifies ID as a disorder associated with disrupted neurochemical communication between nerve cells in the brain mediated by the excitatory neurotransmitter, L-glutamic acid (L-Glu). In this grant application, we will study the impact of missense mutations found in the genes of patients with ID that encode the AMPA receptor (AMPAR), which is an abundantly expressed neurotransmitter receptor activated by L-Glu. Since AMPARs mediate almost all fast excitatory signaling in neuronal circuits, deficits in their function would be expected to have detrimental effects on the developing and adult brain. The proposed experiments will uncover how missense mutations disrupt AMPAR function and thus will offer an entirely new insight into the molecular origins of ID. Furthermore, information gleaned from our work will provide a valuable framework to develop clinical strategies for the treatment and eventual cure of ID.