Mary B. Kennedy

Title: Synaptic Nanomachines

 

Abstract: Information is stored in the brain by formation of new neuronal networks.  Two major adjustments contribute to their formation; changes in the electrical properties of neurons and changes in the strengths of synapses. Over the last three decades, we have learned a great deal about the postsynaptic molecular machinery that underlies activity-dependent changes in synaptic strength of glutamatergic synapses in the CNS.  Much of the machinery is located in the postsynaptic density and we are beginning to learn how its precise spatial organization influences regulation of synaptic strength.  The study of the workings of this complex nanomachinery is an example of the new paradigm called “systems biology” and requires both new ways of thinking about synaptic mechanisms and new computational techniques.  Understanding synaptic nanomachines will allow us to decipher the precise rules that govern modulations of synaptic strength, such as LTP and LTD, in different synapses throughout the brain.

It is possible to construct an approximate model of the arrangement of some of the principle molecular players in the postsynaptic density (PSD).  A first order calculation shows that the numbers of AMPA and NMDA-type glutamate receptors associated with the PSD in a medium- sized mushroom spine are relatively small.  For example, the area of a circular PSD 400 nm in diameter is ~125,600 nm².  The diameter of an AMPA or NMDA-type glutamate receptor (from X-ray crystallography) is ~10 nm.  Thus, ~ 1200 glutamate receptors could be  tightly packed into the membrane adjoining a 400 nm PSD.  Because there are both AMPA and NMDA-type receptors in PSD's of this size, the upper boundary on the number of each kind of receptor is ~ 600.  Electrophysiological measurements suggest that the numbers of AMPA and NMDA- receptors are actually about 10 times smaller, on the order of ~50-60 of each type in a 400 nm PSD.  This leaves ~ 110,00 nm²  for other transmembrane molecules including Trk receptors, cadherins, integrins, and various metabotropic receptors, as well as small numbers of voltage or Ca²⁺ regulated ion channels. 

Transmembrane receptors and ion channels at the postsynaptic site are linked to a dense web of structural proteins, appropriately called scaffold proteins, comprising the PSD-95/SAP, Homer, and Shank/ProSAP families.  Each of these proteins can bind five to twenty other specific regulatory proteins and the signaling machinery organized by the scaffolds is believed to be quite dynamic. We don’t yet have precise pictures of the variety of complexes in the PSD, comparable, for example, to our picture of the structure of a ribosome.  However, biochemists have measured the sizes and relative concentrations of many of the most critical signaling enzymes in the spine.  For example, a medium sized mushroom spine contains ~ 300 dodecameric holoenzymes of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and ~ 30 molecules of the Ca²⁺/calmodulin-dependent protein phosphatase calcineurin.  Influx of Ca²⁺ through NMDA receptors activates these two enzymes; one popular hypothesis holds that the ratio of their activation determines whether activity causes a glutamatergic synapse to be potentiated or depressed.  Little is known about the precise arrangements of these two critical enzymes and how their arrangements influence their activation by NMDA receptors, or their modulation by metabotropic receptors. 

In collaboration with the Sejnowski and Harris labs, we are comparing experiments to stochastic, spatially explicit kinetic simulations, built in the program MCell, to enhance our understanding of the design and function of the synaptic signaling nanomachines.

Bio-sketch: Dr.Kennedy's work focuses on synaptic plasticity and involves study of the functions of the signaling machinery in the postsynaptic density as well as the development of computer simulations of synaptic signaling to aid our understanding of how the large number of signaling molecules present at the synapse may work together. She is the Allen and Lenabelle Davis Professor of Biology at the California Institute of Technology (Caltech) and has been on the faculty since 1981. She was awarded the Ipsen Foundation Prize in Neuronal Plasticity, together with Drs. Eckhart Gundelfinger and Morgan Sheng, in 2006. Mary Kennedy is the founding director of the Center for Integrative Study of Cell Regulation, at Caltech. The center scientists’ work include development of algorithms for identifying, locating, and determining the shape and orientation of key proteins in high-resolution cryo-electron microscopic images of cells, and creation of computer programs to simulate complex biochemical signaling pathways in neuronal synapses.  Dr. Kennedy is leading a program focusing on the modeling of biochemical mechanisms in brain synapses to better understand the chemistry of learning and memory.