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People/Faculty
Morgan Sheng, M.B.B.S., Ph.D.
Menicon Professor of Neurobiology
Investigator, Howard Hughes Medical Institute

Deparment of Brain and Cognitive Sciences
Building: 46-4303
Email: msheng@mit.edu

The Molecular Basis of Brain Plasticity

The brain is a massive network of electrically active cells (neurons) that communicate with each other via specialized cell junctions (synapses). Throughout development and in adult life, the brain responds to experience by adjusting the strength of communication at individual synapses and by changing the physical pattern of synaptic connections between neurons. So information can be stored by the nervous system in the form of altered structure and chemistry of synapses, and/or by the formation of new synapses and the elimination of old ones. This so-called “plasticity” of brain synapses is believed to be the basis of learning and memory. 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 govern synapse formation, growth and elimination. By using biochemical, genetic and imaging approaches to study the dynamic organization of synapses, we hope to reveal the fundamental molecular mechanisms by which the brain modifies itself and adapts to experience.

In a “bottoms-up” approach, we are systematically characterizing the individual protein components of synapses and elucidating how these proteins interact with each other to make up the synaptic junction. Synapses consist of a presynaptic neuron that releases a chemical messenger (neurotransmitter) across a narrow gap to stimulate the postsynaptic neuron. Our focus is on the postsynaptic side of excitatory synapses, which use glutamate as the neurotransmitter. Attached to the postsynaptic membrane is a specialized microscopic structure called the postsynaptic density (PSD). The PSD contains the receptors for the neurotransmitter glutamate (glutamate receptors), of which there are three major classes: NMDA receptors, AMPA receptors, and metabotropic glutamate receptors. Associated with these glutamate receptors are numerous scaffold proteins and enzymes that mediate postsynaptic signaling. Using mass spectrometry and electron microscopy we are measuring the copy number of specific molecules in the PSD and imaging the three dimensional structure of protein complexes in the PSD. Our goal is to reach a quantitative three dimensional description of the molecular architecture of the postsynaptic side of the synapse.

We have mapped the network of proteins and signaling pathways that connect glutamate receptors to the interior of the neuron. By differential activation of postsynaptic signaling pathways, specific patterns of synaptic stimulation can lead to either strengthening (long-term potentiation; LTP) or weakening (long-term depression; LTD) of synaptic transmission. A central puzzle has been how activation of one class of glutamate receptor (the NMDA receptor) and influx of the same second messenger (Ca2+ ions) can lead to opposite effects on synaptic strength (LTP versus LTD). Recent work from our lab (in collaboration with Dr. Yu Tian Wang. HHMI International Scholar, University of British Columbia , Canada ) has suggested that different subtypes of NMDA receptors (which differ in their subunit composition) may be involved in LTP versus LTD. We are trying to understand in detail how different NMDA receptor subtypes activate different signaling pathways in synapses, focusing on the hypothesis that the cytoplasmic tails of the NR2A and NR2B subunits of NMDA receptors bind to, and are thereby coupled to, distinct signaling proteins.

What are the specific functions of the individual components of the PSD? We are taking several approaches to address this question for the key PSD proteins. First, we can overexpress the protein in neurons and examine its effects on synapse morphology and function. Second, we can introduce into neurons “dominant negative” mutants of the protein that should poison the activity of the endogenous normal protein. Thirdly, we can specifically suppress the expression of the protein in neurons by a method called “RNA interference”. Finally, we can disrupt the gene by genetic recombination and create a mutant mouse lacking the specific protein. In this last case, we can evaluate the importance of the gene in terms of behavior and cognitive function (for instance, how the mutant mouse performs in learning and memory tasks).

Using such approaches we are investigating the function of a subset of PSD proteins in the regulation of dendritic spines, which are tiny protrusions found on the branches of many neurons. Dendritic spines are specialized morphological 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. The size of spines correlates with the strength of synapse. It is believed that changes in dendritic spine number and morphology reflect synaptic plasticity, particularly changes in synaptic connections between neurons.

Along the same lines, we are studying several recently identified PSD proteins that are involved in postsynaptic signal transduction, focusing on guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) that regulate small GTPases like Ras, Rap, Rho and Arf, as well as their downstream protein kinases, the MAP kinases. The involvement of these and related signaling mechanisms in LTP and LTD is of particular interest. In addition, we are interested in the highly regulated mechanisms in neuronal dendrites that control the mobility and/or degradation of PSD proteins. For instance, the distribution of the major PSD scaffold PSD-95 is regulated by phosphorylation on a specific serine residue, and the postsynaptic RapGAP called SPAR is degraded upon phosphorylation by the activity-inducible protein kinase Plk2. The detailed mechanisms underlying these processes are being pursued using molecular, mouse transgenic, microscopic imaging, proteomic and electrophysiological techniques.

In concert, the above signaling pathways orchestrate the functional and morphological changes that underlie synaptic plasticity. Our goal is to understand the biochemical actions of these pathways and how they work together to mediate the remarkable plasticity of synapses and the brain. Ultimately, we wish to understand the physiological significance of specific synaptic proteins and specific postsynaptic signaling events in animal behavior and cognition. Improved understanding of basic synaptic biology will illuminate the mechanisms that underlie human neurological disease and mental illness, many of which are manifestations of aberrant synaptic development or function.

Passafaro M, Nakagawa T, Sala C, Sheng M. (2003) Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature 424:677-681.

Pak DTS, Sheng M. (2003) Targeted Protein Degradation and Synapse Remodeling by an Inducible Protein Kinase. Science 302:1368-73. [Epub 2003 Oct 23.]

Lee SH, Simonetta A, Sheng M. (2004) Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43:221-36.

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

Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Walz T, Hayashi Y, Sheng M. (2004) Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron 44:453-67.

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

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

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. 8:458-467. Epub 2005 Mar 6.

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 2005 Jun 2;46(5):745-60.

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

Tada T, Sheng M. Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol. 2006 Feb;16(1):95-101. Epub 2005 Dec 19.

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 2006 Jan 19;49(2):175-82.

Cheng D, Hoogenraad CC, Rush J, Ramm E, Schlager MA, Duong DM, Xu P, Rukshan S, Hanfelt J, Nakagawa T, Sheng M , Peng J. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum. Mol Cell Proteomics 2006 Jun;5(6):1158-70. Epub 2006 Feb 28.