"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.
Neuronal processes are structurally distorted in individuals with neurological disorders. Their structural diversity in normal brains must be measured to understand functional consequences of such distortions. Investigative tools will be improved to measure core subcellular structures regulate synaptic load, especially during long-term potentiation, a well-studied cellular mechanism of learning and memory.
|Watson, Deborah J; Ostroff, Linnaea; Cao, Guan et al. (2016) LTP enhances synaptogenesis in the developing hippocampus. Hippocampus 26:560-76|
|Bartol, Thomas M; Bromer, Cailey; Kinney, Justin et al. (2015) Nanoconnectomic upper bound on the variability of synaptic plasticity. Elife 4:e10778|
|Harris, Kristen M; Spacek, Josef; Bell, Maria Elizabeth et al. (2015) A resource from 3D electron microscopy of hippocampal neuropil for user training and tool development. Sci Data 2:150046|
|Bell, Maria Elizabeth; Bourne, Jennifer N; Chirillo, Michael A et al. (2014) Dynamics of nascent and active zone ultrastructure as synapses enlarge during long-term potentiation in mature hippocampus. J Comp Neurol 522:3861-84|
|Cao, Guan; Harris, Kristen M (2014) Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice. J Neurophysiol 112:1916-24|
|Edwards, John; Daniel, Eric; Kinney, Justin et al. (2014) VolRoverN: enhancing surface and volumetric reconstruction for realistic dynamical simulation of cellular and subcellular function. Neuroinformatics 12:277-89|
|Kuwajima, Masaaki; Mendenhall, John M; Harris, Kristen M (2013) Large-volume reconstruction of brain tissue from high-resolution serial section images acquired by SEM-based scanning transmission electron microscopy. Methods Mol Biol 950:253-73|
|Bourne, Jennifer N; Chirillo, Michael A; Harris, Kristen M (2013) Presynaptic ultrastructural plasticity along CA3â†’CA1 axons during long-term potentiation in mature hippocampus. J Comp Neurol 521:3898-912|
|Kuwajima, M; Spacek, J; Harris, K M (2013) Beyond counts and shapes: studying pathology of dendritic spines in the context of the surrounding neuropil through serial section electron microscopy. Neuroscience 251:75-89|
|Kinney, Justin P; Spacek, Josef; Bartol, Thomas M et al. (2013) Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil. J Comp Neurol 521:448-64|
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