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.