Neuroscience
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Dendritic spines, the bulbous protrusions that form the postsynaptic half of excitatory synapses, are one of the most prominent features of neurons and have been imaged and studied for over a century. In that time, changes in the number and morphology of dendritic spines have been correlated to the developmental process as well as the pathophysiology of a number of neurodegenerative diseases. ⋯ This review will highlight traditional approaches to the imaging of dendritic spines and newer approaches made possible by advances in microscopy, protein engineering, and image analysis. The review will also describe recent work that is leading researchers toward the possibility of a systematic and comprehensive study of spine anatomy throughout the brain.
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Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by a progressive loss of cognition and the presence of two hallmark lesions, senile plaques (SP) and neurofibrillary tangles (NFT), which result from the accumulation and deposition of the β-amyloid peptide (Aβ) and the aggregation of hyperphosphorylated tau protein, respectively. Initially, it was thought that Aβ fibrils, which make up SP, were the root cause of the massive neurodegeneration usual found in AD brains. ⋯ In this review, we address some of the important evidence, which has led to the Aβ oligomer-centric hypothesis as well as some of the key findings concerning the effects of Aβ oligomers on synapses at a morphological and functional level. Understanding how Aβ oligomers target synapses provides an important framework for ongoing AD research, which can lead to the development of successful therapeutic strategies designed to alter or perhaps reverse the course of the disease.
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Because dendritic spines are the sites of excitatory synapses, pathological changes in spine morphology should be considered as part of pathological changes in neuronal circuitry in the forms of synaptic connections and connectivity strength. In the past, spine pathology has usually been measured by changes in their number or shape. A more complete understanding of spine pathology requires visualization at the nanometer level to analyze how the changes in number and size affect their presynaptic partners and associated astrocytic processes, as well as organelles and other intracellular structures. ⋯ Renewed interest in ssEM has led to recent technological advances in imaging techniques and improvements in computational tools indispensable for three-dimensional analyses of brain tissue volumes. Here we consider the small but growing literature that has used ssEM analysis to unravel ultrastructural changes in neuropil including dendritic spines. These findings have implications in altered synaptic connectivity and cell biological processes involved in neuropathology, and serve as anatomical substrates for understanding changes in network activity that may underlie clinical symptoms.
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Given the rapid rate of population aging and the increased incidence of cognitive decline and neurodegenerative diseases with advanced age, it is important to ascertain the determinants that result in cognitive impairment. It is also important to note that much of the aged population exhibit 'successful' cognitive aging, in which cognitive impairment is minimal. ⋯ Structural changes of neurons and dendritic spines during aging, and the functional consequences of such changes, remain poorly understood. Elucidating the structural and functional synaptic age-related changes that lead to cognitive impairment may lead to the development of drug treatments that can restore or protect neural circuits and mediate cognition and successful aging.
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Dendritic spines provide a compartment for assembly and functional organization of synaptic machinery that plays a fundamental role in neuronal communication and neuroplasticity. Studies in humans as well as in animal models have demonstrated abnormal spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of spines is thought to contribute to the behavioral deficits caused by stress exposure. ⋯ Here we review the evidence from brain imaging and postmortem studies demonstrating that depression is accompanied by structural and functional alterations of cortical and limbic brain regions, including the prefrontal cortex, hippocampus and amygdala. In addition, we present more direct evidence from basic research studies that exposure to stress alters spine morphology, function and plasticity and that antidepressants, particularly new rapid acting agents, reverse these effects. Elucidation of the signaling pathways and molecular mechanisms that control spine synapse assembly and plasticity will contribute to a better understanding of the pathophysiology of depression and development of novel, more effective therapeutic agents.