Grant: Project Grant

Rett syndrome is a neurological disorder caused by mutations in a gene called MECP2 that controls many other genes to regulate the formation and function of brain circuits. Female patients get one X from their father, one from their mother but genes from only one of the two X chromosomes in each cell are expressed so half of the brain cells of female patients have a normal copy (expressing their mother's X) while the other half have a deficient copy of the gene (expressing their father's X). Patients suffer from many deleterious cognitive and motor symptoms including epileptic seizures. Given that the Rett brain is comprised of a mixture of mutant and non-mutant neurons a "one-size-fits-all" approach to pharmacological intervention may be inappropriate. Drug-based therapies for these patients have to be compatible with brain circuits composed of a mixture of mutant and non-mutant neurons. This project seeks to understand how the presence of neurons with mutated genes affects the properties of normal and mutated neurons and the circuits they form. Our work investigates how the higher parts of the brain (neocortex) receive and modulate information from the part of the brain that gates sensory information called the thalamus. In Rett syndrome the balance between neural excitation and inhibition in many circuits is disrupted due to incorrect wiring and improper levels of neurotransmitter receptors. Acetylcholine is a transmitter that modulates circuit functions and has different kinds of effects depending on whether receptors for this transmitter are over- or under-expressed and in which neuron types they are dysregulated. This project uses a combination of advanced single neuron anatomical and electrophysiological recording techniques to understand how Mecp2 mutation affects how mutant neurons perform in cortico-thalamic circuits, how acetylcholine receptor expression is altered and how this affects the function of cortico-thalamic circuits.