Information transfer between neurons in the brain occurs at specialized structures called synapses. Excitatory synapses, those using glutamate as a neurotransmitter, are a critical component of the neuronal circuits governing higher brain functions like learning, memory and emotion. Dysfunctional glutamatergic synapses mediate or exacerbate psychiatric diseases such as Schizophrenia and bipolar disorder as well as acute and chronic neurodegenerative diseases such as stroke, Alzheimer’s and Parkinson's disease. At the molecular level, scaffold proteins direct information flow through this signal transduction network. Our goal is to learn the rules of molecular organization at synapses by reconstituting the postsynaptic density on membranes and watching it in action with single molecule microscopy. Our research incorporates methodology from chemistry, cell biology, physics, neuroscience and computation.
Reconstituting the Postsynaptic Density
The postsynaptic density (PSD) contains all the receptors, channels and enzymes involved in neurotransmitter detection and signaling. The PSD got its name because proteins pack so tightly into the postsynapse that it saturated early electron micrographs. The proteins in the PSD form a self-organizing nanomachine that is tuned and rewired by our experiences. Following in the classical tradition of biophysics, we are recreating these molecular machines from first principles.
Single Molecule Spectroscopy
The mind endows each individual with a uniqueness that comes from personal experience. The same is true at the molecular level where each protein can have a unique history and environment. To understand dynamic proteins and their heterogeneous assemblies requires appreciation of their molecular individuality and adaptability. The Bowen Lab takes a single molecule approach to the structural biology of the postsynaptic density.
Intrinsic Disorder and Supertertiary Structure
Protein function arises from its structure. Proteins with a single function often have a unique 3D structure. Signaling proteins need to respond to a dynamic environment, which requires a dynamic structure. Such intrinsically disordered proteins (IDPs) may lack structure entirely or contain folded domains linked together into a supertertiary structure. Studying IDPs comes with a unique set of challenges but their prevalence in the postsynaptic density speaks to their importance.