Dendritic spines are morphological specializations that protrude from the main shaft of neuronal dendrites. Typically 0.5-2 µm in length (but up to 6 µm in the CA3 region of the hippocampus) 1,2 , dendritic spines are found at a linear density of 1-10 spines per µm of dendritic length in mature neurons 3 . Most excitatory synapses in the mature mammalian brain occur on spines, and a typical mature spine has a single synapse located at its head. So, dendritic spines represent the main unitary postsynaptic compartment for excitatory input. Most principal neurons of either glutamatereleasing (for example, pyramidal neurons) or GABA (γ-aminobutyric acid)-releasing (for example, Purkinje neurons) type bear dendritic spines, but many classes of neuron do not (for instance, most GABA-releasing interneurons). Spiny neurons are rarely found in lower organisms (for example, Drosophila melanogaster and Caenorhabditis elegans), indicating that spines evolved to accommodate the more complex functions of 'advanced' nervous systems, such as the mammalian brain. In this review, we cover the essential background to dendritic spines, but focus on recent advances in our understanding of spine plasticity, and the molecular mechanisms that regulate spine formation and shape. The structure of dendritic spinesDendritic spines come in a wide variety of shapes and sizes, ranging in volume from less than 0.01 µm 3 to 0.8 µm 3 (reviewed in REFS 1,4). On the basis of detailed anatomical studies of fixed brain tissue, dendritic spines have been classified by shape as thin, stubby, mushroom-and cup-shaped 5-7 (FIG. 1). However, the arbitrary classification of spines into these four categories underestimates the great heterogeneity of spine morphology, which is apparent even on a single dendrite 8,9 . It can also bias us towards a misleadingly static view of spine morphology. Live imaging studies have revealed that spines are remarkably dynamic, changing size and shape over timescales of seconds to minutes and of hours to days (see below and FIG. 1). So, fixed structures seen under the electron microscope are probably snapshots of spines in morphological transition. Two-photon time-lapse imaging of motile spines showed that, in developing neurons,~50% of observed spine-like protrusions maintained their morphological classifications over several hours, whereas the other half switched classes 10 . As spine motility is developmentally regulated 11 , fewer transitions between categories presumably occur in mature neurons.In addition to varying in shape and size, spines also differ in their content of organelles and specific molecules. In general, large spines have proportionately larger synapses and contain a greater diversity of organelles (FIG. 2). The postsynaptic density (PSD) is an electron-dense thickening of the membrane that is found at the synaptic junction, which is usually located at the head of the spine. The PSD occupies 10% of the surface area of the spine, and is exactly Dendritic spines are tiny protrusions that receive excitatory ...

Cholesterol/sphingolipid microdomains (lipid rafts) in the membrane are involved in protein trafficking, formation of signaling complexes, and regulation of actin cytoskeleton. Here, we show that lipid rafts exist abundantly in dendrites of cultured hippocampal neurons, in which they are associated with several postsynaptic proteins including surface AMPA receptors. Depletion of cholesterol/sphingolipid leads to instability of surface AMPA receptors and gradual loss of synapses (both inhibitory and excitatory) and dendritic spines. The remaining synapses and spines in raft-depleted neurons become greatly enlarged. The importance of lipid rafts for normal synapse density and morphology could explain why cholesterol promotes synapse maturation in retinal ganglion cells (Mauch et al., 2001) and offers a potential link between disordered cholesterol metabolism and the synapse loss seen in neurodegenerative disease.

The number and shape of dendritic spines are influenced by activity and regulated by molecules that organize the actin cytoskeleton of spines. Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting. Knockdown of cortactin protein by short-interfering RNA (siRNA) results in depletion of dendritic spines in hippocampal neurons, whereas overexpression of cortactin causes elongation of spines. In response to synaptic stimulation and NMDA receptor activation, cortactin redistributes rapidly from spines to dendritic shaft, correlating with remodeling of the actin cytoskeleton, implicating cortactin in the activity-dependent regulation of spine morphogenesis.