Overview
The Molecular Basis of Synaptic Plasticity.  We seek to understand the molecular and cellular mechanisms underlying the ability of the brain to change in response to experience and to store information over long time periods, such as occur during development and for learning and memory. Our research is focused on the molecular regulation of synaptic structure and function, using genetic, biochemical, imaging and behavioral approaches in vitro and in vivo.

Research Summary
The brain is a massive network of electrically active cells (neurons) that communicate with each other via specialized cell junctions (synapses). Throughout development and adult life, the brain responds to experience by adjusting the strength of communication between synapses and by changing the spatial pattern of connections between neurons. Long-term information can be stored by the nervous system in the form of altered structure and chemistry of synapses or by formation of new synapses. This so-called “plasticity” of synapses is believed to be the basis of learning and memory in the brain. Because of their central importance in information processing and storage, it is important to understand the molecular architecture of synapses and the cellular processes that control synapse formation/elimination and synaptic strength.

What are the protein components of synapses and what functions do they perform in synaptic transmission and plasticity? We have continued the systematic characterization of proteins and signaling pathways that regulate the structure and function of the postsynaptic specialization. Increasingly, we use mass spectrometry “proteomic” approaches to identify as well as quantify synaptic proteins and their post-translational modifications. Currently, we believe there are 200-300 proteins that make up the postsynaptic specialization.

Among the major postsynaptic proteins are the receptors for the neurotransmitter glutamate (glutamate receptors), of which there are three major classes: NMDA receptors, AMPA receptors, and metabotropic glutamate receptors. These glutamate receptors associate with different intracellular protein complexes by interacting with distinct scaffolding proteins. The receptor-associated protein complexes direct the output of glutamate receptor signaling and contain numerous enzymes and scaffold proteins. NMDA receptor signaling is particularly important for synaptic plasticity. We have found that the outcome of NMDA receptor activation (e.g. synaptic potentiation versus depression, CREB phosphorylation versus dephosphorylation) depends on the subunit composition of NMDA receptors, at least in part because the major subunits NR2A and NR2B bind to distinct signaling proteins.

Another major focus of our lab is the regulation of dendritic spines, which are tiny actin-rich protrusions found on the branches of many neurons. Dendritic spines are specialized compartments on which excitatory synapses are formed, and these fascinating structures change in size and shape depending on a wide variety of factors such as brain activity, neurological disease, hormonal cycles and aging. Changes in dendritic spine number and morphology are an important component of structural plasticity of synapses. We are interested in the specific molecules that control the formation, morphology and motility of dendritic spines. Shank is a major postsynaptic scaffold protein that interfaces between NMDA receptors and regulators of the actin cytoskeleton. Overexpression of Shank induces bigger mature spines of mushroom shape. We have generated knockout mice that lack Shank1 and found that they have smaller synapses and spines, but surprisingly, improved performance in a spatial learning task.

Synapses and their constitutent proteins undergo constant and regulated turnover. Formation and elimination of synapses occurs throughout life, but particularly actively during maturation of the brain. We are studying the activity-dependent molecular mechanisms that regulate synapse formation and elimination, with the hope of identifying signaling pathways that might go awry in disorders of the nervous system (neurodegeneration, psychiatric illness).

Selected Publications
Ryu J, Liu L, Wong TP, Wu DC, Burette A, Weinberg R, Wang YT, Sheng M. A critical role for myosin IIb in dendritic spine morphology and synaptic function. Neuron Jan 19;49(2):175-82. (2006)

Hoogenraad CC, Milstein AD, Ethell IM, Henkemeyer M, Sheng M. GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nat Neurosci. Jul;8(7):906-15. (2005)

Kim MJ, Dunah AW, Wang YT, Sheng M. Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron Jun 2;46(5):745-60. (2005)

Dunah AW, Hueske E, Wyszynski M, Hoogenraad CC, Jaworski J, Pak DT, Simonetta A, Liu G, Sheng M. (2005) LAR Receptor Protein Tyrosine Phosphatases in the Development and Maintenance of Excitatory Synapses in Hippocampal Neurons. Nat Neurosci. Apr;8(4):458-67. Epub Mar 6. (2005)

Nakagawa T, Cheng Y, Ramm E, Sheng M*, Walz T. Structure and different conformational states of native AMPA receptor complexes. Nature 433:545-549. (*co-corresponding author). (2005)

Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci. 5:771-81. (2004)

Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873-87. (2004)

Sheng M, Kim MJ. Postsynaptic Signaling and Plasticity Mechanisms. Science. 298:776-780. (2002)

Search PubMed for Sheng lab publications.

Click image for large view and discussion.