Overview: Molecular Structure and Function of Central Nervous System Synapses

Memories are stored in the brain as connected neurons "encoding" simultaneous events and impressions.  Activation of one of the connected neurons can lead to activation of all of them.  Formation of new memories requires the formation of new connections among neurons.  One way the brain accomplishes this is to strengthen synapses among neurons that fire together during an event.

Neurons communicate through synapses that release chemical transmitters to activate a target neuron. Many transmitters can also initiate biochemical changes in the signaling machinery of the synapse itself.  The biochemical changes can either increase or decrease the size of the signal produced by the synapse when it fires again. This is called "synaptic plasticity." 

Our brains have evolved complex mechanisms for controlling the circumstances under which such changes will occur.  For example, one of the receptors for the excitatory amino acid glutamate (the NMDA-type glutamate receptor), triggers an increase in the strength of an active synapse only when simultaneous activation of several synapses causes the postsynaptic neuron to fire an action potential. This "plasticity rule" is used to form memories.

Our lab is studying biochemical signal transduction systems in central nervous system synapses.  We have focused on a complex of signaling proteins, called the postsynaptic density (PSD), located just underneath excitatory receptors in the central nervous system. We showed that it contains signal transduction molecules that can control the sensitivity of transmitter receptors, the size of receptor clusters, and perhaps the integrity of the adhesion junction that holds presynaptic terminals in place. 

Employing a combination of microchemical and recombinant DNA methods, we have determined the structure of several proteins associated with the PSD. We are presently studying the associations of these proteins with each other and their specific roles in controlling synaptic transmission.  Our ultimate goal is to illuminate the ways that synapses change their strength to encode memories. 

Because many (we think most) of the important signaling molecules in the PSD have now been identified and sequenced, we are turning our attention to learning how they work together to create the delicate mechanisms of synaptic plasticity.  Thus, one aspect of our work involves study of the functions of the signaling machinery in the postsynaptic density.  Another major aspect is 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.