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The role of neuroligins in synapse formation, maintenance, and plasticity

  • Author(s): Shipman, Seth
  • Advisor(s): Nicoll, Roger A
  • et al.
Abstract

Possession of a nervous system endows an organism with a substantial range of behavioral abilities owing to a diverse class of excitatory cells in the brain termed neurons and, more importantly, the connections between them. Primary sensory information flows through neural circuits, being shaped and processed as it does, resulting in perception, thought, decision, and action. The processing power of any individual neuron, while considerable, cannot account for such complex behavior. Rather, it is an emergent property of an interconnected system of neurons, the primary unit of connection being the chemical synapse. These synapses permit fast, moment-to-moment transmission of information between cells without compromising the electrical integrity of an individual cell, allowing integration of information can take place at both a cellular and circuit level. Healthy connections allow for split-second decisions, breathtaking insights, and incredible feats of coordination, whereas disrupted transmission can lead to devastating diseases such as schizophrenia and autism. These synaptic sites of connection between neurons are anatomical as well as functional - requiring an initial physical interaction between cells in the process of establishing a meaningful connection. This thesis begins with an inquiry into these anatomical aspects of a synapse. Specifically, I present evidence for the requirement of synaptic adhesion molecules in the formation and plasticity of synapses. I take one family of postsynaptic adhesion molecule, neuroligin, as a model for the class to test its specific function with regard to synaptogenesis and plasticity. I identify and describe three major functions of the protein, each dependent on a specific structural component: one, differentiation of the presynaptic terminal, dependent on dimerization, achieved via the trans-synaptic clustering of the presynaptic adhesion molecule neurexin; two, recruitment of postsynaptic components during synaptic assembly, dependent on a previously uncharacterized region of the postsynaptic intracellular domain, achieved via the scaffolding of the postsynaptic site; and three, specification of synaptic subtype, dependent on alternative splicing of the extracellular domain, achieved via a trans-synaptic protein binding code. Finally, I examine the distribution of synapses along a dendritic arbor and the determination of relative synaptic weight as it relates to the electrical integrative properties of a cell.

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