Thomas Biederer PhD
Biochemistry of membrane proteins; Molecular and cellular neuroscience; Synapse formation
Current ProjectsWe aim to determine the molecular mechanisms of synapse formation in the developing CNS of vertebrates. Our goal is to identify and characterize the events that initiate synapse formation, and the steps that lead to its completion. To achieve this goal, we pursue three aims. First, we examine the role of adhesion and signaling molecules in CNS synapse formation. These experiments involve biochemical characterization of SynCAM, and the functional analysis of its extracellular interactions in cultured hippocampal neurons. Second, we determine the intracellular SynCAM interactions driving synaptic membrane specializations. Here, we purify and characterize intracellular binding partners of SynCAM from brain. Third, we analyze the site of SynCAM action in pre- and postsynaptic membrane specialization. This set of studies is conducted in cultured neurons, and also in genetically altered mice to manipulate synapse formation in vivo and to test effects on synaptic plasticity and brain development.
Synapse Formation in the Central Nervous System:
The development of synapses is necessary to establish a functional nervous system. Neurons form new synapses both during early development and in the adult brain. This process allows information to be transmitted from the pre- to the postsynaptic cell. Our studies aim to address on the molecular level how synaptic specializations are assembled at distinct plasma membrane sites from a limited number of components. Our goal is to identify and characterize the events that initiate synapse formation and the steps that lead to its completion.
Characterization of Synaptic Cell Adhesion Molecules:
Synaptic cell adhesion molecules mediate the physical contact between pre- and postsynaptic neurons. During synaptogenesis, these trans-synaptic interactions align and demarcate the membrane surfaces of the pre- and postsynaptic neuron. Subsequently, membrane specializations are formed on both sides of the synapse: The presynaptic terminal holds synaptic vesicles that are ready for release, and the postsynaptic membrane contains the matching neurotransmitter receptors.
Significance: Synapse formation and modulation are likely to play central roles in learning and memory. Importantly, synaptic dysfunctions occur in human illnesses like mental retardation and Alzheimer's disease. Molecular insight into synaptogenesis in the healthy brain will allow development of approaches to improve or treat these human neurodevelopmental and neurodegenerative disorders.
Extensive Research Description
Our goal is to understand the molecular mechanisms of synapse formation in the vertebrate brain. In development, neurons form pre- and postsynaptic membrane specializations at sites of contact to assemble synapses. We know little about this critical process, in contrast to our understanding of structure and function of mature synapses. To address this question, we focus on the roles of SynCAM proteins. SynCAMs are a family of synaptic cell adhesion molecules that assemble into adhesive complexes at nascent synapses. They bridge the synaptic cleft and drive formation of new synapses. SynCAMs therefore are likely to act early in synapse differentiation. Our questions are first, how they demarcate sites of future synaptic specializations, and second, how synapse formation is coordinated across the synaptic cleft in time and space. In our studies, we employ biochemical, molecular biological, and optical imaging techniques. In addition, we analyze this process in vivo using mouse genetics.