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. This research is highly relevant to human brain diseases because it is becoming clear that synaptic dysfunction and synapse loss are cardinal features of autism, neurodegeneration (e.g. Alzheimers disease) and psychiatric illness (schizophrenia, depression).

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 200-400 proteins that make up the postsynaptic specialization, and we use genetic, RNAi and electron microscopy methods to characterize the functions of major proteins as well as their physical contribution to the 3-dimensional structure of the postsynaptic density.

An emerging area is the regulation of postsynaptic components by phosphorylation and dephosphorylation. We have identified many phosphorylation sites in the postsynaptic density by mass spectrometry and are studying the functional significance of these modifications for synaptic strength and structure. For example, phosphorylation of the scaffold protein PSD-95 at two different sites differentially regulates its stability and abundance at postsynaptic sites, resulting in bidirectional effects on synaptic transmission.

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. These phenotypes might be relevant to human autism spectrum disorder, which have been linked to Shank mutations.

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. Using live imaging and biochemistry, 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
Seeburg DP, Feliu-Mojer M, Gaiottino J, Pak DT, Sheng M.

 Critical role of CDK5 and Polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron. May 22;58(4):571-83. (2008)

Hung AH, Futai K, Sala C, Valtschanoff J, Ryu J, Woodworth M, Kidd FL, Sung CC, Miyakawa T, Bear MF, Weinberg FJ, Sheng M. Smaller Dendritic Spines, Weaker Synaptic Transmission but Enhanced Spatial Learning in Mice Lacking Shank1. J Neurosci  Feb 13;28(7):1697-708. (2008)

Kim MJ, Futai K, Jo J, Hayashi Y, Cho K, Sheng M. Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95. Neuron Nov 8;56(3):488-502. (2007)

Tada T, Simonetta A, Batterton M, Kinoshita M, Edbauer D, Sheng M. Role of septin cytoskeleton in spine morphogenesis and dendrite development in neurons. Curr Biol. Oct 23;17(20):1752-8. (2007)

Sheng M, Hoogenraad CC. The Postsynaptic Architecture of Excitatory Synapses: A More Quantitative View. Annu Rev Biochem 2007;76:823-47.
Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci. 5:771-81. (2004)
Sheng M, Kim MJ. Postsynaptic Signaling and Plasticity Mechanisms. Science. 298:776-780. (2002)

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