Dendritic spine formation and stabilization
Introduction
Morphological alteration of excitatory synapses is one of the most important and efficient cellular mechanisms underlying plasticity of neural functions [1, 2]. In the central nervous system, the majority of glutamatergic excitatory inputs are received by dendritic spines of postsynaptic neurons. Spines are specialized protrusions emerging from neuronal dendrites, with characteristic bulbous enlargements at their tips (spine heads). Dendritic spines are first formed in early postnatal life, shaped up by the animal's experience, and maintained into adulthood. Time-lapse imaging of spine dynamics visualized with genetically engineered fluorescent proteins revealed that the spines are not static, but actively move, and alter their morphology continuously even in the adult brain, reflecting the plastic nature of synaptic connections [3, 4, 5, 6, 7]. Hippocampal synapses undergo structural changes in size and shape after long-term potentiation in vitro and experience in vivo [8, 9, 10]. Additionally new spines are formed, which become functional synapses and eventually replace non-activated ones [9, 11, 12•, 13••, 14]. Finally, abnormal spine structures are often associated with various neurological disorders such as Fragile X, Down, and Rett syndromes [15].
Careful electron microscopic observations uncovered the fine structures and subcellular organelles of dendritic spines and identified a unique dense thickening, the so-called postsynaptic density (PSD), under the surface membrane of spine heads. The PSD is a postsynaptic specialization usually apposed to synaptic vesicle-containing presynaptic boutons. A number of biochemical and molecular biological studies have been performed to elucidate molecular compositions of spines, especially in the PSD, and provided comprehensive lists of functional molecules including cell recognition/adhesion molecules, neurotransmitter receptors, ion channels, intracellular adaptor proteins, cytoskeletal proteins, kinases/phosphatases, GTP-binding proteins and extracellular proteases [16]. Gain- and loss-of-function analyses revealed that many of these molecules are involved in various aspects of spine development and functions. This is particularly the case of cell adhesion molecules, such as cadherin/catenin, neurexin/neuroligin, Eph/ephrin, nectins, SALMs, SynCAMs, which play roles in the formation, maturation, and stabilization of spine synapses [17] (Figure 1). Some of these molecules are also present in another type of dendritic protrusions called dendritic filopodia. We review here some recent findings regarding the mechanisms of synaptogenesis, focusing on two types of dendritic protrusions: filopodia and spines (Figure 2).
Section snippets
Dendritic filopodia
Dendritic filopodia are long, thin, headless, and most often PSD-free protrusions abundantly present in developing neurons. They can still be found later in the adult brain, but mainly under specific conditions such as induction of plasticity, following ischemia or during regeneration after neuronal injury [18, 19, 20]. Dendritic filopodia are highly motile and flexible structures, with an average lifetime in the range of minutes to hours [6, 21, 22]. Due to their high motility, they are
Molecular control of filopodia fate
In contrast to a wealth of knowledge on dendritic spines, little is known about the molecular and cellular mechanisms underlying the formation and maintenance of dendritic filopodia, the transformation from filopodia to spines, and the physiological significance of dendritic filopodia. However, several functional molecules have been recently identified, which regulate the formation of dendritic filopodia (Table 1). These molecules can be classified into two categories: ‘accelerators’ and
Telencephalin: a brake of spine maturation
TLCN is a cell adhesion molecule belonging to the immunoglobulin (Ig) superfamily. TLCN gene is present only in mammalian species. The Ig-like domains of TLCN most closely resemble those of intercellular adhesion molecules (ICAMs) that serve various important functions in cell–cell interactions of the immune system such as the formation of immunological synapses between T lymphocytes and antigen-presenting cells [34]. TLCN is the only neuronal member of the ICAM family and thus also called
Synapse formation through spine growth
In more mature tissue, time-lapse imaging has shown that new protrusions may also directly appear as spines [5, 11]. This process, which occurs within minutes, probably accounts for about half of all protrusions formed in young (1–3 weeks old) hippocampal slice cultures [11, 19, 22]. Typically, these new spines have long necks and small heads, which sometimes makes them difficult to distinguish from filopodia, except that they are less motile. In young neurons, new spines and filopodia are
Spine maturation and synaptic plasticity
Once a contact is made, the challenge of the new synapse is to become stabilized, a process that is likely to be regulated by neural activity [44]. Newly formed spines are usually thin and elongated and in general have a small head. They have often been referred to as learning spines in opposition to classical mushroom-shape spines that are representing more stable structures [2]. During this early phase of stabilization, when newly formed spines acquire a PSD, their spine head enlarges, a
Conclusion
Dendritic spine formation and stabilization as a functional excitatory synapse remains a mystery with complex mechanisms involving a multiplicity of steps, regulations and molecules. Our current understanding suggests the existence of two parallel tracks, one based on the growth of filopodia and predominantly active in early phases of development, where regulation of motility by molecules such as Ephrins and Telancephalin plays a critical role for the transformation into spine synapses, and a
References and recommended reading
Papers of particular interest published within the period of review have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
The authors thank Yutaka Furutani and Susanne C Hoyer for critical comments on the manuscript. This work was supported by Takeda Science Foundation to YY., a Grant-in-Aid for Scientific Research on Priority Area (Molecular Brain Science) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to YY, and Swiss National Science Foundation and European program Promemoria to DM.
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