**Dendritic Spine Modifications in Brain Physiology Dendritic Spine Modifications in Brain Physiology**

DOI: 10.5772/intechopen.73326

#### Jun Ju and Qiang Zhou Jun Ju and Qiang Zhou Additional information is available at the end of the chapter

[69] Traka M, Podojil JR, McCarthy DP, Miller SD, Popko B. Oligodendrocyte death results in immune-mediated CNS demyelination. Nature Neuroscience. 2016;**19**(1):65-74

[70] Oluich LJ, Stratton JA, Xing YL, Ng SW, Cate HS, Sah P, Windels F, Kilpatrick TJ, Merson TD. Targeted ablation of oligodendrocytes induces axonal pathology indepen-

[71] Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM. An inducible caspase 9 safety switch for T-cell therapy. Blood.

[72] Caprariello AV, Batt CE, Zippe I, Romito-DiGiacomo RR, Karl M, Miller RH. Apoptosis of oligodendrocytes during early development delays myelination and impairs subsequent responses to demyelination. The Journal of Neuroscience. 2015;**35**(41):14031-14041

[73] Caprariello AV, Mangla S, Miller RH, Selkirk SM. Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination. Annals of Neurology.

[74] Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the

[75] Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL. A regenerative approach to the treatment of multiple sclerosis. Nature.

[76] Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nature

[77] Najm FJ, Lager AM, Zaremba A, Wyatt K, Caprariello AV, Factor DC, Karl RT, Maeda T, Miller RH, Tesar PJ. Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells. Nature Biotechnology.

[78] Najm FJ, Madhavan M, Zaremba A, Shick E, Karl RT, Factor DC, Miller TE, Nevin ZS, Kantor C, Sargent A, Quick KL, Schlatzer DM, Tang H, Papoian R, Brimacombe KR, Shen M, Boxer MB, Jadhav A, Robinson AP, Podojil JR, Miller SD, Miller RH, Tesar PJ. Drugbased modulation of endogenous stem cells promotes functional remyelination in vivo.

newly forming lesion. Annals of Neurology. 2004;**55**(4):458-468

dent of overt demyelination. The Journal of Neuroscience. 2012;**32**(24):8317-8330

2005;**105**(11):4247-4254

146 Neuroplasticity - Insights of Neural Reorganization

2012;**72**(3):395-405

2013;**502**(7471):327-332

2013;**31**(5):426-433

Medicine. 2014;**20**(8):954-960

Nature. 2015;**522**(7555):216-220

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73326

**Abstract**

An essential feature for an organism to survive is to adapt and learn. Studies in the past decades have revealed that synaptic plasticity is a key cellular mechanism underlying learning and memory functions in the adult, and the refinement of neural connections during development. Memory and refinement of connections can last for a long period of time, and hence requires the corresponding structural changes to take place. Alterations in dendritic spine morphology (enlargement or shrinkage) and/or spine density (increase or decrease) have been shown to occur with synaptic modifications, and have been proposed to enable persistent, long-term modifications of synapses. In this chapter, we will review the basics of spine plasticity and its functional contributions to synaptic modification, with focus on modifications of spine morphology (enlargement and shrinkage).

**Keywords:** spine formation, synaptic plasticity, AMPA receptor trafficking, cytoskeleton, long-term potentiation, long-term depression

### **1. Introduction**

Dendritic spines are small protruding structures from the dendrites, around 1 μm in diameter. Spines are the primary site of excitatory inputs onto neurons and about 90% of excitatory synapses occur on spines of the excitatory neurons in the adult cortex [1].

Based on the size, spine head size and spine neck length, they can be roughly divided into three distinct types: mushroom, thin and stubby spine. Mushroom type spines have large spine heads and narrow spine necks, thin spines have small spine heads and thin spine necks, while stubby spines bear no distinction between spine heads and necks [2, 3]. In reality, the distribution of spines is not in these distinct sets but in a continuous distribution.

A major component of dendritic spines is cytoskeleton, which is critical to the structure and function of spines. Cytoskeletons consist of actin filaments and microtubules. Actin filaments

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

are highly enriched in spine heads, while microtubules are found mostly in the dendritic shafts [4, 5]. Actin filaments inside spines are of two pools, G-actin and F-actin. G-actin is a monomer form of actin and F-actin is the polymer form, while they are found in the tip and base of spines, respectively [6]. Actin filaments bind to the scaffold proteins such as PSD-95 and Shanks, which anchor receptors and signaling molecules at the synapses [7]. Actin filaments are dynamic since actin monomer dissociates from the pointed end while new actin monomers are recruited into the barbed end. Certain actin-binding proteins regulate this dynamic process [8].

showed that axonal fibers made synaptic contacts with long filopodia, which subsequently were transformed into mature spines [25]. Durand et al. reported during the first postnatal week in rats, synapses on the excitatory neurons are functional and plastic in the absence of dendritic spines [26]. Hence synaptic function and plasticity can take place without spines. After induction of long-term enhancement of synaptic connections in area CA1, new spines appeared on the postsynaptic dendrite [27]. Maletic-Savatic found that with axonal inputs activation, these small filopodia-like protrusions enlarged and became dendritic spines [28]. For those filopodia that do not connect with axonal inputs, they did not turn into mature spines and were absorbed back into dendrites [12]. Interestingly, increase of spine synapse might inhibit the mobility of nearby filopodia on the same dendrite and diminish the formation of synapses [29]. These results indicate that synapse formation or strengthening promotes the formation or maturation of spines, and lend support for the notion that synapse

Dendritic Spine Modifications in Brain Physiology http://dx.doi.org/10.5772/intechopen.73326 149

Do spines form from filopodia, or from existing synapses on the dendritic shafts? In mature cultures, some stable spines could emerge without going through the dynamic filopodia stage [12]. The series sample analysis in young hippocampal area CA1 also revealed that most of synapses are on dendritic shafts, with rare synapses on stubby and mushroom spines [3]. Despite all this, the transformation from dendritic shaft synapses to spines has not been supported by direct observations [30]. On the other hand, several *in vitro* studies revealed that during the initial 1–2 weeks in culture, the long and headless filopodia bear no synaptic contacts associated with the presynaptic axons. Over the subsequent 4 weeks, these dynamic filopodia turned into stable, mushroom-like spines [29, 31, 32]. Fiala et al. also found that in the hippocampal CA1, synapses were present on both filopodia and dendrites. From PN1 to PN12, the number of shaft synapses and filopodia synapses was decreased, while the number of stubby and spine synapses was significantly increased [25]. Thus, it is likely that during early development, shaft synapses are the dominant form of synaptic contact. With development, and likely the need for increasing contact area, spine synapse replace shaft synapses to become the major form of synapses, at least in the adult cortex. Recently, shaft synapses are shown to define the locations where dendritic spines are formed [30] (**Figure 1**), providing more evidence for the transition from shaft synapse to spine synapse as a major process in

The initial surge of spine genesis leads the generation of more spines than what eventually is retained in the adult brain, and pruning of excessive spines after spine genesis allows a better adaptation to the environment [33]. This pruning process could be evoked by lowfrequency glutamatergic stimulation and requires activation of NMDA receptors [34–36].

**Figure 1.** Dendritic spines are derived from filopodia with the assistance of shaft synapses. (1) presynaptic axon forms synapses with dendritic shaft. (2) a dendritic protrusion occurs adjacent to the dendritic shaft synapse. (3) the dendritic protrusion contacts with the presynaptic axon and eventually a mushroom dendritic spine is generated. Modified from [30].

genesis occurs prior to spine genesis.

synapse formation and maturation.

Spines are dynamic features in that they are in a constant motion (termed morphing), and their sizes fluctuate around a mean value [9, 10]. Dendritic filopodia are highly motile and flexible, and their lifetime is on the order of minutes to hours [11, 12]. This high motility may allow filopodia to explore the space around them in search for potential presynaptic inputs to form connections [13]. To understand this dynamic nature and to monitor these changes accurately, two-photon imaging has become an invaluable tool. With two-photon imaging, spine morphology and dynamics can be studied in much more details using time-lapse and repetitive imaging. This approach has revealed spine modifications under physiological or pathological conditions or events [14–16] and has greatly advanced our understanding of spine function and allowed in-depth study on the underlying structure–function relationship. During brain development dendritic spines are dynamic in their genesis and elimination, while in adolescence spines show much higher elimination than formation which results in a net spine loss or pruning. In contrast, the rate of spine genesis and elimination in adult is much lower and about equal, and this balance maintains the stability of spine density [17, 18].

Spine is considered as a unique calcium compartment, because the transfer of electrical charge is limited by the spine neck. The length of spine neck controls the degree of interaction between spines and their parent dendrite. In general, short spines and parent dendrites show similar responses to glutamate, while long spines exhibit faster and larger responses [19]. Spine plasticity is evidenced by their rapid (on the order of seconds) and persistent (for months to years) changes in response to physiological or pathological stimuli. Large spines has been suggested to be the site of stable long-term memory storage [1] while filopodia are considered by most to be an immature form of spine. Filopodia may transform into mature spines or are eliminated [20]. Hence, we define spine plasticity in two forms: alterations in their morphology/size and alterations in their density. We note that both forms of plasticity reflect modification of synaptic connections. In neurodegenerative and psychiatric diseases, spine density and spine morphology are altered, and changes in spine density and morphology may at least partially account for altered brain functions in these diseases [1, 21–24]. Therefore, better understanding of spine pathology may provide better therapeutic intervention.

In this chapter, we will discuss signaling mechanisms underlying the formation and maintenance of spines, plasticity of spine morphology and its relationship to modification of synaptic strength.
