Elsevier

Biological Psychiatry

Volume 55, Issue 12, 15 June 2004, Pages 1121-1127
Biological Psychiatry

Neuroscience perspective
Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease

https://doi.org/10.1016/j.biopsych.2003.10.006Get rights and content

Abstract

Psychiatric and neurologic disorders ranging from mental retardation to addiction are accompanied by structural and functional alterations of synaptic connections in the brain. Such alterations include abnormal density and morphology of dendritic spines, synapse loss, and aberrant synaptic signaling and plasticity. Recent work is revealing an unexpectedly complex biochemical and subcellular organization of dendritic spines. In this review, we highlight the molecular interplay between functional domains of the spine, including the postsynaptic density, the actin cytoskeleton, and membrane trafficking domains. This research points to an emerging level of analysis—a microanatomical understanding of synaptic physiology—that will be critical for discerning how synapses operate in normal physiologic states and for identifying and reversing microscopic changes in psychiatric and neurologic disease.

Section snippets

Disruptions of dendritic spines are associated with psychiatric and neurologic disorders

A broad variety of psychiatric diseases and neurologic disorders are accompanied by patterns of spine disruption (Huttenlocher, 1970, Fiala et al., 2002b). The major hereditary mental retardation syndromes, Fragile X and Down, are accompanied by changes in spine morphology, in particular a decrease in mature spines and an increase in elongated protrusions that resemble spine precursors called filopodia (Irwin et al., 2000, Kaufmann and Moser, 2000). Chronic administration of the

Control of synaptic function by spine morphology

Spine morphology is intimately linked to synaptic function (Sorra and Harris, 2000, Hering and Sheng, 2001, Yuste and Bonhoeffer, 2001), and so alteration of spine shape and size during disease likely has diverse functional effects. Most conspicuously, larger spines have larger synapses and support stronger synaptic transmission (El-Husseini et al., 2000, Murthy et al., 2001). In addition, spine morphology plays an important role in synaptic plasticity, since the large spine head and the

The actin cytoskeleton and spine shape

Spine morphology is determined by a number of factors, the most well established of which is the actin cytoskeleton. Spines and their filopodial precursors are rich in filamentous actin and display substantial actin-dependent motility (Matus 2000). Many signals such as extracellular guidance cues and growth factors that control dendritic morphology do so via the Rho GTPases (Nakayama and Luo 2000), a family of highly conserved proteins that link extracellular signals to control of the actin

The microanatomical organization of spines

Although spine size and shape have long been recognized as key attributes of synapse function that are altered during disease (Fiala et al 2002b), new techniques and recent findings are defining the arrangement of molecular components and membrane domains within spines—what we term the “microanatomy” of spines. Indeed, spines contain highly specialized protein complexes, structural elements, intracellular membrane compartments, and cell surface microdomains, which together orchestrate molecular

Protein trafficking within spines

The strict positioning of synaptic proteins and neurotransmitter receptors at the PSD is the most celebrated example of spine microanatomical organization. More recently, however, it has become clear that spines contain additional specialized domains that are devoted to delivering, maintaining, or removing synaptic proteins from the PSD proper. In particular, many synaptic receptors are dynamically transported to and from the postsynaptic membrane, and controlling the number of receptors

Microanatomical localization of endocytic zones in dendritic spines

The spatial configuration of clathrin coats at the light microscopic level has given the first insight into the organization of protein trafficking machinery within spines. Remarkably, clathrin coats in spines are present at a stereotypical location in relation to the synapse (Blanpied et al 2002). Clathrin puncta almost never form directly at the synapse but instead are segregated from the synaptic membrane, typically forming several hundred nanometers away (Figure 1C, 1D). The presence and

The role of endocytosis in addiction

Receptor endocytosis plays notable roles in the physiologic basis of drug abuse and addiction. Many drugs of abuse, including the opiates, cannabinoids, and nicotine, produce their effects as agonists at cell surface receptors. Activation of many receptors leads to their removal from the membrane by clathrin-mediated endocytosis (Claing et al., 2002, Sorkin and Von Zastrow, 2002, Dani et al., 2001, St. John and Gordon, 2001). This endocytic control is involved in receptor down-regulation and

New technology and future directions

Further progress linking the disorder of spines in disease with biochemical or molecular therapeutic targets will require a more complete understanding of the cell biological foundations of spine function and plasticity. A number of new tools are permitting rapid advances in these areas. The twin technologies of confocal/multiphoton microscopy and GFP protein labeling for imaging live neurons allow visualization of single spines at high spatial resolution in culture, in tissue slices, and in

Acknowledgements

We thank Juliet Hernandez, April Horton, and Michele Pucak for helpful comments on the manuscript. This work is partially supported by the National Institutes of Health (MDE) a grant from the Ruth K. Broad Biomedical Research Foundation (MDE), and a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (TAB).

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