Regulation of Glutamatergic Synapses in Development and Disease

Dynamic changes in synaptic communication between neurons underlie normal processes such as brain development and learning and memory and are dysregulated in developmental, psychiatric and neurological disorders such as autism, schizophrenia, drug addiction, mood disorders, and Alzheimer's disease. The focus of our research is the identification of the molecular mechanisms that regulate glutamatergic synapses in order to better understand brain function and the etiology of neurological and psychiatric disorders.

Neuronal circuits are formed during development and can undergo modifications throughout adulthood, for example in response to learning. The basic unit of neuronal circuitry and site of contact between neurons is the synapse. Glutamatergic synapses constitute the majority of excitatory synapses in the brain and their inputs are received by dendritic spines, which are actin-rich structures crucial for the regulation of synaptic function. Structural and functional alterations of glutamatergic synapses, including abnormalities in dendritic spines density and morphology, synapse loss, and altered synaptic signaling and plasticity have been associated with developmental, psychiatric, and neurologic disorders such as autism, schizophrenia, and Alzheimer's.

An integral component of dendritic spines is the postsynaptic density (PSD), a cytoskeletal structure which organizes the postsynaptic signaling machinery. The PSD is molecularly complex and contains many classes of proteins including adhesion molecules and scaffolding, cytoskeletal, and signaling proteins. The PSD also contains NMDA and AMPA receptors, two types of glutamate receptors that play critical roles in learning and memory, neurological and psychiatric disorders. Studies from many laboratories have indicated that dendritic spines and their PSD are dynamic structures that are modified by neuronal activity, underlying LTP and LTD, two forms of synaptic plasticity related to learning and memory.

My lab is interested in understanding the molecular and functional organization of dendritic spines in normal physiological conditions and in identifying alterations associated with synaptic dysfunction. We are using genetic, pharmacological, cellular, molecular, and imaging approaches to gain insight into the postsynaptic networks that regulate NMDA and AMPA receptor signaling and the morphology and stability of dendritic spines.

 Current projects in the laboratory:

• Regulation of postsynaptic signaling and protein trafficking
• Regulation of trans-synaptic adhesion and actin cytoskeleton dynamics
• Synaptic dysfunction in brain disorders
  

	Rat hippocampal neuron in culture (above) expressing b-Gal (to visualize the dendrites) and immunostained for b-Gal (green) and PSD-95 (red), a protein enriched in dendritic spines.
	The postsynaptic density (dark area, above) is a highly organized, dynamic structure that contains NMDA and AMPA receptors (left). We are interested in identifying the molecular mechanisms that regulate NMDA and AMPA receptors signaling and their alterations in neurodegenerative and psychiatric disorders.