Molecular Mechanisms Underlying the Structural Plasticity of Central Synapses

Thomas Biederer, Ph.D.

Yale University School of Medicine

Department of Molecular Biophysics and Biochemistry
Funded in December, 2008: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Using Cellular Imaging to Identify Molecules Involved in Synaptic Plasticity in Learning

Investigators will use cellular imaging techniques to examine the changes that occur at the molecular level at the synapse, the junction between two brain cells, when the cells communicate to facilitate learning.  

Brain cells communicate with one another by passing an excitatory or inhibitory electrochemical signaling molecule, called a “neurotransmitter,” from one cell to another at the synapse.  Synaptic changes, termed “brain plasticity,” occur in response to neural activity.  Such activity-dependent modifications in the strength of synaptic connections occur by altering the number, structure, and molecular composition of the connections.  This can take numerous forms.  For example, a pre-synaptic (transmitting) neuron can increase the amount of a neurotransmitter it releases, to be picked up by a neighboring neuron’s dendritic spines.  These are tiny branches that have receptors on their surface which take up the neurotransmitter and send it on to the nerve cell body.  Conversely, the post-synaptic (receiving) neuron might decrease the number of receptors it has on its dendritic spines, conveying less excitatory neurotransmitter to the nerve cell.  Or, dendritic spines might retract altogether and stop the signal.   Such synaptic brain plasticity in the hippocampus is crucial for learning and memory to occur.  What controls these changes?

The investigators hypothesize that activity-dependent changes in synaptic structure and function are controlled by cell adhesion molecules, and that alterations in this plasticity underlie aberrant synapse structures associated with developmental disorders.  They will test the first part of this hypothesis.  Cell adhesion molecules belong to a family of proteins involved in cellular interactions.  The proteins are embedded in cell membranes, where their outer surfaces adhere to similar proteins on other cells at synapses while another portion of the protein extends inside the brain cell and responds to internal changes such as increased neuronal firing rates.  In laboratory mice, the researchers will use cellular two-photon, confocal and fluorescence imaging to study different cell adhesion molecules.  They will use molecular genetic techniques to increase and decrease levels of each candidate protein to determine which types, in response to an excitatory neurotransmitter, modify dendritic spines in the hippocampus.  Proteins that appear to be important then will be studied in transgenic mice exposed to a learning activity known to activate hippocampal neurons, and determine which of the candidate proteins affects synaptic dynamics and learning.

ABSTRACT

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Molecular Mechanisms Underlying the Structural Plasticity of Central Synapses

Neurons communicate with each other through synapses, and the strength of these synaptic connections can be locally altered to direct the flow of information within the central nervous system.  Specifically, synapses have the capacity to actively adapt their morphology in response to activity, or inactivity.  This allows for changing synaptic connections in an activity-dependent manner, which is a key property of synapses that underlies homeostatic balance of neuronal networks as well as learning and memory.

The molecular mechanisms underlying these dynamic changes are not sufficiently understood.  The central hypothesis of this proposal is that synapse-organizing adhesion and signaling molecules and their downstream effectors control the structural and functional plasticity of synapses in the brain.  Gaining insights into the basis of structural plasticity at synapses is of great clinical relevance, as aberrations in synapse morphology are prevalent in human neurodevelopmental disorders and neurological diseases.

The objective of our proposed studies is to determine the molecular mechanisms of synaptic structural plasticity in the central nervous system of vertebrates.  Specifically, we will analyze activity-dependent changes in the morphology and composition of spines, which are the postsynaptic elements of excitatory synapses.  Presynaptic functional changes in response to activity levels will be additionally determined.  Select synapse-organizing candidate molecules will first be analyzed whether they affect these activity-dependent plasticity processes of synapses in live cultured neurons.  Their functions will then be validated in vivo.  Imaging of synaptic structural plasticity will be performed using live two-photon microscopy as well as standard fluorescence imaging of live samples, and confocal microscopy.  The research proposed here will advance our understanding of molecular and cellular neuroscience, and aims to direct the development of novel therapeutic strategies for disorders of the human brain.

INVESTIGATOR BIOGRAPHIES

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Thomas Biederer, Ph.D.

Thomas Biederer, Ph.D., received his undergraduate degree in biochemistry from the Freie Universität in Berlin, Germany.  He later earned a Ph.D. in biology from the Humboldt-Universität zu Berlin.  Dr. Biederer then moved to the University of Texas Southwestern Medical Center at Dallas to pursue postdoctoral training under the mentorship of Dr. Thomas Südhof.  While at UT Southwestern, he explored synapse formation in the vertebrate central nervous system.  A member of the Yale faculty since 2003, Dr. Biederer is an associate professor in the Department of Molecular Biophysics and Biochemistry, where his laboratory investigates the molecular basis of synapse formation and organization.  Recently, his laboratory identified synaptic cell adhesion molecules (SynCAMs) of the immunoglobulin superfamily, which are sufficient to drive presynaptic differentiation and also promote neurotransmission. 

The major research focus in Dr. Biederer’s laboratory is on the role of SynCAMs, as well as other novel synaptic adhesion proteins, in the formation and organization of synapses through trans-synaptic interactions.  Dr. Biederer’s work is strongly motivated by his interests in the biochemical mechanisms underlying the differentiation of neuronal membranes, the neurobiological development and plasticity of neuronal networks in the human brain, as well as the biomedical relevance of altered synapse organization to human neurodevelopmental and neurodegenerative disorders. In addition to the 2008 award from The Dana Foundation’s Program in Brain and Immuno-imaging, Dr. Biederer received a Basil O’Connor Starter Scholar Research Award from the March of Dimes Foundation in 2005, and a Leadership Chair of Research Award from The Brain Tumor Society in 2004.