Structural dynamics of dendritic spines in memory and cognition Haruo Kasai 1 , Masahiro Fukuda 1 , Satoshi Watanabe 1 , Akiko Hayashi-Takagi 2 and Jun Noguchi 1 1 Laboratory of Structural Physiology, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, and Center for NanoBio Integration, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan 2 Department of Psychiatry and Behavioral Neurosciences, Johns Hopkins University School of Medicine, Baltimore MD 21287, USA Recent studies show that dendritic spines are dynamic structures. Their rapid creation, destruction and shape- changing are essential for short- and long-term plasticity at excitatory synapses on pyramidal neurons in the cerebral cortex. The onset of long-term potentiation, spine-volume growth and an increase in receptor traf- ficking are coincident, enabling a ‘functional readout’ of spine structure that links the age, size, strength and lifetime of a synapse. Spine dynamics are also implicated in long-term memory and cognition: intrinsic fluctu- ations in volume can explain synapse maintenance over long periods, and rapid, activity-triggered plasticity can relate directly to cognitive processes. Thus, spine dynamics are cellular phenomena with important implications for cognition and memory. Furthermore, impaired spine dynamics can cause psychiatric and neu- rodevelopmental disorders. Dendritic spines On pyramidal neurons in the cerebral cortex, excitatory synapses terminate at spines, which are short protrusions joined to the main dendrite by a thin neck. Discovered in the 19th century and intensely scrutinized in the 20th century, dendritic spines are found in higher animals [1,2] and some insects [3,4]. Spines exist only on certain types of neurons, including pyramidal neurons in the cortex, medium spiny neurons in the basal ganglia and Purkinje cells in the cerebellum. Spines are more abundant in higher brain regions and highly variable in shape. Moreover, dendritic spines are the most actin-rich struc- tures in the brain [5,6], and their morphology and density are abnormal in several mental disorders [7]. The best-known example of input-specific, activity-de- pendent synaptic plasticity—Donald Hebb’s canonical basis for learning and memory [8] —is long-term poten- tiation (LTP) of spine synapses in the hippocampus [9]. The link between LTP and spine structure was suggested by the finding that the size of the postsynaptic density (PSD) is related to the size of the spine head [10] and the number of AMPA-type glutamate receptors within it [11–13]. These ultrastructural studies, however, could not determine the functional state of a spine. This structure–function relationship was first established in 2001 using two-photon uncaging of a caged–glutamate compound [14–20]. Later reports showed that spine enlargements are associated with LTP in single identified spines (Figure 1a) [21], indicating that Hebb’s learning rule applies even at the level of a single synapse. Many studies have since con- firmed that the induction of LTP or long-term depression (LTD), another form of activity-dependent plasticity, induces structural plasticity of spines in stimulated den- dritic branches [22–30]. Given the apparent stability in vivo of dendritic and axonal arbors at low magnification [31–33], the properties that govern spine dynamics over the long-term could play a major role in reorganizing cortical circuitry throughout life [34,35]. In fact, spines are frequently generated and elimi- nated even in the adult neocortex, and these events have been suggested as substrates for stable memory formation [35–38]. Both formation and enlargement of spines are important during synaptic rearrangements in the visual cortex that follow sensory deprivation [39]. It is important to note that spine structural dynamics include broader phenomena than LTP/LTD. Namely, they include the generation and elimination of spines [31,32,40– 42], and long-term, activity-independent fluctuations (described in detail below) (Figure 1b) [42]. In addition, spines become larger in response to the force of actin polymerization [43], which occurs within seconds [21] of LTP induction [44]. Spines seem to display expansive force continuously to maintain their shape and function [43]. These findings suggest that spine synapses are not just electrochemical but also mechanical in nature. The purpose of this article is to present the new findings on spine dynamics that can be extrapolated to a broad spectrum of higher-order brain functions. We summarize the relationships between spine structural dynamics and functional plasticity, explain the long-term maintenance of spine structures, propose an explanation for the impair- ment of spine dynamics in mental disorders and introduce the possible relationships between rapid spine dynamics and cognitive processes. Activity-dependent structural plasticity of dendritic spines and receptor trafficking At the level of the dendritic spine, structural dynamics and receptor trafficking both contribute to functional plasticity. For example, spine enlargement occurs within a minute (Figure 1a) [21], a time course that matches the rapid Review Corresponding author: Kasai, H. (hkasai@m.u-tokyo.ac.jp) 0166-2236/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2010.01.001 121