Distance-Dependent Structure and Function of Neuronal Dendrites

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DESCRIPTION (provided by applicant): "Distance-Dependent Structure and Function of Neuronal Dendrites" Neuronal dendrites, axons and synapses are structurally distorted in individuals with mental retardation and other neurological disorders. Their structure also differs greatly in normal brains. The overall goal of this research is to characterize this structural variation to learn how neurons regulate, sustain, and alter synaptic connectivity as brain function develops and changes with learning and pathology. The approach is three-dimensional reconstruction and quantification through serial section electron microscopy (EM). Long-term potentiation (LTP), a robust cellular model for learning, is exploited to investigate subcellular components including microtubules for transport; smooth endoplasmic reticulum for calcium regulation and protein trafficking; polyribosomes, Golgi outposts, and spine apparatuses for local protein synthesis; recycling and sorting endosomes for redistribution and degradation of membranes and proteins; and mitochondria for ATP production and calcium regulation. Our new discovery that total synaptic load, measured as summed synaptic area, is evenly balanced along dendrites and scales with caliber, suggests that heterosynaptic competition for intrinsic resources may control how many synapses a dendrite or axon can sustain along its length. Even when synapses enlarge during LTP, the total synaptic load in healthy brains is re-equilibrated by 2 hr, leaving fewer but larger synapses along the potentiated dendrites. Furthermore, only ~20% of the axons that pass next to dendrites actually form synaptic contacts, suggesting that similar intrinsic resource limitations might govern the number and size of synapses supported along axons. A rigorous plan is proposed to assess whether core structures scale with synapse number and size along dendrites of different calibers and positions in the dendritic arbor, and their associated axons during LTP. Novel approaches in EM tomography, large EM field imaging and analysis are being developed to improve the quality of the measurements, increase efficiency, and to share content-rich data broadly.This work is at the forefront of the systematic study of intrinsic mechanisms to control inter-neuronal connectivity and synaptic function.Such knowledge is crucial to design effective treatments for many neurological disorders.