Cell Mol Neurobiol DOI 10.1007/s10571-016-0348-1

REVIEW PAPER

Modulation of Synaptic Plasticity by Exercise Training as a Basis for Ischemic Stroke Rehabilitation Jingjing Nie1 • Xiaosu Yang1

Received: 3 December 2015 / Accepted: 11 February 2016 Ó Springer Science+Business Media New York 2016

Abstract In recent years, rehabilitation of ischemic stroke draws more and more attention in the world, and has been linked to changes of synaptic plasticity. Exercise training improves motor function of ischemia as well as cognition which is associated with formation of learning and memory. The molecular basis of learning and memory might be synaptic plasticity. Research has therefore been conducted in an attempt to relate effects of exercise training to neuroprotection and neurogenesis adjacent to the ischemic injury brain. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved in modulation of synaptic plasticity by exercise training. This review shows the pathological process of synaptic dysfunction in ischemic roughly and then discusses the effects of exercise training on scaffold proteins and regulatory protein expression. The expression of scaffold proteins generally increased after training, but the effects on regulatory proteins were mixed. Moreover, the compositions of postsynaptic receptors were changed and the strength of synaptic transmission was enhanced after training. Finally, the recovery of cognition is critically associated with synaptic remodeling in an injured brain, and the remodeling occurs through a number of local regulations including mRNA translation, remodeling of cytoskeleton, and receptor trafficking into and out of the synapse. We do provide a comprehensive knowledge of synaptic plasticity enhancement obtained by exercise training in this review.

& Xiaosu Yang [email protected] 1

Department of Neurology, Xiang Ya Hospital, Central South University, Xiang Ya Road 87, Changsha 410008, Hunan, China

Keywords Ischemic stroke
Exercise training
Synaptic plasticity
Synaptic dysfunction
Rehabilitation

Introduction Stroke is a leading cause of morbidity and mortality worldwide. Ischemic stroke accounts for approximately 80 % of all strokes and generally accompanied by severe disability (Truelsen et al. 2003). Cerebral ischemia leads to diverse pathophysiological changes including brain edema (Park et al. 2015), neuronal loss (Damodaran et al. 2014), cognitive dysfunction, and synaptic dysfunction (Park et al. 2015; Bazan et al. 2005; Kamchatnov et al. 2014), resulting in cognitive decline and memory impairment (Khatri and Man 2013; Neumann et al. 2013; Hofmeijer et al. 2014; Li et al. 2013; Tjepkema-Cloostermans et al. 2014). Recovery of motor function after stroke can be modified by postinjury experience, but most of surviving patients exhibit persistence of the motor dysfunctions and cognitive disorder (Nowak 2008) even after rehabilitative therapy. Hence, choosing an appropriate approach is determinant for a successful rehabilitation, recovery of motor function cognitive competence, and improvement of life quality of the surviving stroke victims. Physical exercise has beneficial effects on brain health and cognition. It uses the processes of energy metabolism and synaptic plasticity to promote brain health, upregulating proteins related to cognitive (Ding et al. 2006) and mitochondrial function (Kirchner et al. 2008). So physical rehabilitation therapy remains the first-line intervention strategy for attenuating chronic impairments in sensorymotor function (Arya et al. 2011). Many studies with humans and animal models have shown the beneficial effects of both voluntary and forced exercises involving

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cognitive and other brain-related tasks for protecting the brain against neurodegenerative disorders (Tajiri et al. 2010; Ploughman et al. 2005; Shimada et al. 2013). Correlations between manipulated motor activity and brain synaptic plasticity in normal and impaired rats have been further demonstrated by Jones et al. (1999). In their study, complex motor skill training can enhance cortical synaptogenesis and improve functional performance. Experimental treatments for stroke often focus on reducing motor impairments; however, cognitive impairments are also common following stroke, but have received less attention. Over the last several decades, there has been growing support for the use of exercise training to enhance recovery of function after stroke. On the other hand, the identification of mechanisms that can amplify, enhance, or strengthen synaptic plasticity represents potential therapeutic tools for enhancing adaptive memories and contrasting the onset and progression of disorders of cognitive functions.

Pathomechanism of Synaptic Dysfunction in Ischemic Stroke Synapses are sites of a specialized cell–cell contact between neuronal cells and represent the major structure involved in chemical neurotransmission in the nervous system. They consist of three main components including the pre- and postsynaptic elements and the surrounding astroglial ensheathment. The term synaptic plasticity covers many different aspects of use-dependent synaptic modifications and is commonly used in a broader sense describing aspects of synaptic signal transmission as well as structural alterations in the molecular make-up of the synapse related to synaptic signaling events. Any intractable neurological conditions, such as stroke, can lead to synaptic signal transmission and structural damage (Huerta and Volpe 2009), which is described as synaptic dysfunction. An acute ischemic stroke occurs when an artery supplying the brain becomes occluded, leading to diverse pathophysiological changes including blood brain barrier (BBB) disruption, brain edema, neuronal cell death, and synaptic loss in brain (Zhao et al. 2007). Aquaporin (AQP) is the water channel protein that facilitates water transport through cell membranes (Agre et al. 2002). Specifically, AQP-1 is permeable only to water and is considered to participate in brain water homeostasis (Zador et al. 2009). In addition, AQP 1 has been reported to be involved in edema formation and cell death in the hippocampus following brain injury (Qiu et al. 2014). Brain edema leads to an imbalance in energy demand and influences on the postsynaptic effects of glutamate (Attwell and Laughlin

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2001) and interruption of synaptic transmission in the penumbra after stroke (Astrup et al. 1981; Symon 1980). Previous studies indicate that cerebral ischemia suppresses the expression of synaptophysin, PSD- 95 which are synaptic markers, and MAP2 that are important in modulating the synaptogenesis (Song et al. 2015). A few minutes after uncompensated brain ischemia, cell death pathways overcome survival-promoting pathways, which leads to neuronal death through three interaction mechanisms: excitotoxicity attributable to excess glutamate, oxidative stress, and stimulation of apoptotic-like pathways (Bano and Nicotera 2007; Lo et al. 2005). And the mechanisms connected to Ca2? dysregulation in ischemia also can induce cell death. It is associated with alterations of Ca2? buffering capacities, deregulation of Ca2? channel activities, and alterations of other Ca2?regulating proteins due to excitotoxicity, perturbed energy metabolism, and oxidative stress. Abnormal cellular Ca2? load can trigger cell death by activating proteases, by reinforcing signals leading to caspase activation, or by triggering other catabolic processes mediated by lipases and nucleases. Increased thrombin has been shown to cause synaptic dysfunction (Maggio et al. 2008, 2013), and previous studies indicate that thrombin activity rises significantly in the ischemic hemisphere reaching peak levels at the ischemic core (Bushi et al. 2015). Furthermore, spatial distribution analysis indicates that high levels of thrombin activity are also detected at peri-infarct areas. Higher thrombin levels promote excitability (Maggio et al. 2013) and cell death at later stages by directly triggering apoptosis (Xi et al. 2006). The fact that high thrombin activity levels in peri-infarct areas have been found also suggests that thrombin may affect the function and fate of periinfarct areas following an ischemic event. Cerebral ischemia reperfusion injury can incur the formation of free radicals accompanied with damage of hippocampus and long-term functional disability of synaptic transmission and further produce learning and memory deficits. And ischemia can also inhibit the synaptic transmission by preventing the production and storage of ATP and neurotransmitter. Furthermore, under cerebral ischemia injury, malfunction of brain Glu system has been suggested to be associated with cognitive impairment of several neurodegenerative diseases and influence learning and memory ability. These insults contribute to excessive synaptic-glutamate accumulation, triggering a series of intracellular biochemical changes and finally inducing neuron death. It is also reported that the way to limit excitotoxicity can be obtained by increasing GABA-mediated inhibition and some inhibitory amino acids in the central nervous system (CNS), such as Gly, have displayed neuroprotection in rat cortical neurons under hypoxia.

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Cerebral cortex, hippocampus, and corpus striatum in the brain are the most vulnerable regions against oxidative stress and hypoxic injury induced by cerebral ischemia (Bano and Nicotera 2007). Hence, we review the modulation of synaptic plasticity in stroke rehabilitation focus on trials about these vulnerable regions.

Effect of Training on Synaptic Plasticity Loss of function attributable to stroke is caused by cell death in infarcted regions as well as cell dysfunction in the areas surrounding the infarct. Some recovery of function occurs spontaneously after stroke in humans as well as in animal models. It is believed that this functional recovery involves phases that change the properties of existing neuronal pathways and neuroanatomical plasticity leading to the formation of new neuronal connections (Wieloch and Nikolich 2006). The basic processes underlying these phases also are involved in normal learning and it has been recognized that functional improvement after CNS injury is a relearning process (Warraich and Kleim 2010). Exercise has protective effects against ischemic stroke (Greenough and Anderson 1991). The nature of enrichment and complex motor activities requires the integration of a variety of input and plastic changes across multiple brain structures in response to behavioral experiences (Greenough and Anderson 1991; Comery et al. 1995). Further study in ischemic animals may provide a valuable insight into mechanisms of functional recovery after stroke and may shape the development of therapeutic rehabilitative strategies. And the effects of exercise on synaptic plasticity are indicated by the increased levels of synaptic structural molecules. The mechanism underlying exercise-induced synaptic plasticity requires the involvement of a myriad of molecules implicated in the maintenance and regulation of brain function, including neurotrophic factors, signal transduction proteins, transcription factors, and synaptic proteins (Cassilhas et al. 2012; Cotman et al. 2007; Ding et al. 2004; Lista and Sorrentino 2010). Mechanisms regulating glutamate receptor activation and intracellular calcium levels are also important for normal synaptic transmission and recovery of synaptic dysfunctions. We assume that exercise may stimulate changes in brain protein synthesis as a part of its effects on plasticity. Effect of Training on Molecular Organization of the Pre- and Postsynaptic Scaffold Scaffold proteins play a major role in many synaptic functions including the trafficking, anchoring, and clustering of glutamate receptors and adhesion molecules. The

expression of proteins associated with nerve plasticity could be enhanced by treadmill training (Tsai et al. 2013). GAP-43 The growth-associated protein GAP-43 is a neuron-specific protein found in high concentrations in growth cones and presynaptic terminals and is closely associated with neuritogenesis, synaptic plasticity, and regenerative processes (Aigner et al. 1995; Oehrlein et al. 1996; Oestreicher et al. 1997). GAP-43 expression in the hippocampus was significantly reduced by stroke injury (Cheon 2015). Upregulation of GAP-43 was found following treadmill running (Tsai et al. 2013). In the process of brain ischemia recovery, an increase in the hippocampal levels of GAP-43 in exercised rats was observed. And the increased expression of GAP-43 may have mediated, at least in part, the prevention of memory loss in the ischemia models. Consistent with previous research, Song-Hee Cheon (Cheon 2015) indicated that increased GAP-43 expression in the hippocampus following skilled reaching training resulted in enhanced cognition and neural plasticity following stroke. And Mizutani proposed that voluntary exercise induced an increase of GAP-43 in cortex surrounding the ischemia accompanied with better functional rehabilitation (Mizutani et al. 2011). Synapsin-I Synapsin-I is a phosphoprotein implicated in neuroplasticity that tethers synaptic vesicles to the actin cytoskeleton and regulates the proportion of vesicles available for release in the presynaptic terminal (Jovanovic et al. 2000). It is involved in both the synaptogenesis and the plasticity of mature synapses by controlling synaptic vesicle trafficking at pre- and post-docking levels (Oestreicher et al. 1997). During development, synapsin I regulates neurite growth and the maturation of synaptic contacts, and it has been shown to regulate axonal elongation and novel synaptic formation (Ferreira et al. 1998; Zurmohle et al. 1996). Thus, locally high level synapsin I is considered to be a marker of synaptic plasticity and neurogenesis and is thought to maintain the high rates of synaptic activity within the neural networks in which it participates (Melloni et al. 1993). Consistently, previous reports have shown that spatial learning increased synapsin I mRNA and protein expression (Gomez-Pinilla et al. 2001) which indicate that synapsin I is associated with learning and memory. Ischemia can cause damage in expression of synapsin I, and in a previous study skilled training induced a long-term increase of synapsin I in sensorimotor cortex of ischemia when compared with controls (Pagnussat et al. 2012). This is not surprising since skilled training is a rehabilitation

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task that associates elaborated motor activity and higher cognitive function. Other physical exercises have a similar effect on synapsin I of ischemia, but the expression of synapsin I is modulated differently depending on the type and volume of exercise (Cassilhas et al. 2012; Ferreira et al. 2011; Vaynman et al. 2004). Synaptophysin Synaptophysin, a major integral glycoprotein attached to the membrane of synaptic vesicles, acts as an important protein in the biogenesis of synaptic vesicles (Thiele et al. 2000) and appears to be involved in the formation of the fusion pore between the vesicle and the plasma membrane (Thiele et al. 2000) as well as in the endocytosis and recycling of synaptic vesicles (Evans and Cousin 2005). In addition, as a marker of the presynaptic nerve terminal density, synaptophysin is essential for the release of neurotransmitter (Greengard et al. 1993). The reduction of synaptophysin has been reported to reduce synaptic plasticity in the brain (Rapp et al. 2004). Yuchuan Ding reported that motor skill training, involving balance and coordination, facilitates a uniquely lateralized synaptogenesis in the thalamus by analyzing the expression of synaptophysin in rats subjected to stroke (Ding et al. 2003). Other reports also demonstrated increased expression of synaptophysin in the hippocampus (Cassilhas et al. 2012; Vaynman et al. 2004), thalamus (Ding et al. 2002), striatum, and substantia nigra (Ferreira et al. 2010) after different exercise regimens. Conversely, 4 weeks of aerobic exercise did not induce significant changes in synaptophysin expression compared with that in all other groups (Fernandes et al. 2013). In agreement with that, hippocampal levels of synaptophysin were not altered after several weeks of forced and voluntary exercise (Ferreira et al. 2011; Hescham et al. 2009; Lin et al. 2015). PSD-95 PSD-95 (also named SAP90), as a postsynaptic marker, is a member of the membrane-associated guanylate kinase family of synaptic molecules and is localized at excitatory synapses (Feyder et al. 2010), mainly at mature glutamate synapses (Yoshii et al. 2011). Postsynaptic density (PSD) proteins are involved in regulation of synaptic function and in the transduction of synaptic signals to the postsynaptic cell (Kennedy 1998; Ziff 1997) by organizing signaling complexes at the postsynaptic membrane. Especially, PSD95 has been implicated in the regulation of ion-channel function, synaptic activity (Dietrich et al. 2005; El-Husseini et al. 2000), intracellular signaling, and finally cognitive impairment (Migaud et al. 1998). In addition, PSD95 protein is implicated in promoting synapse stability and

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makes synaptic contacts more stable in neurons (Feyder et al. 2010) Besides, the amount of PSD-95 can also regulate the balance between the number of inhibitory and excitatory synapses (Levinson and El-Husseini 2005). Research reports on the correlation of PSD-95 and diverse brain disease syndrome (Tsai et al. 2012; Cao et al. 2013) have implicated that the loss of PSD-95 results in severe cognitive decline due to loss of neurons and synaptic disruption and loss of synaptic connection (Han and Kim 2008; Terry et al. 1991). On the one hand, its content can be diminished after brain lesions (Hu et al. 1998) and, on the other hand, behavioral training increases PSD-95 expression (Dietrich et al. 2005; Xu et al. 2009; Gandhi et al. 2014). In the previous study, we found that the immune content of PSD-95 is markedly increased in the sensorimotor cortex after focal ischemia and skilled training (Pagnussat et al. 2012). Analogously, involuntary, forced, and voluntary exercises are equally capable of inducing increased levels of PSD-95 in the hippocampus after stroke (Lin et al. 2015). Interestingly, in Shih, P.C.’s report, the levels of PSD-95 increased significantly in lowintensity exercise group in bilateral hippocampus of ischemia brain (Shih et al. 2013) which indicated that lowintensity exercise may result in better synaptic plasticity and spatial memory performance than high-intensity exercise after brain ischemia. When localized in postsynaptic terminals, PSD-95 overexpression is sufficient for multiinnervated dendritic spine (MIS) generation (Giese et al. 2015), which is a spine that receives typically two presynaptic inputs. In accordance with the foregoing, different exercise programs have demonstrated experience-dependent increases in dendritic spine density in the hippocampus and cerebellum (Stranahan et al. 2007). Influence of Training on the Regulatory Protein of Synaptic Plasticity Upregulated expression of BDNF and abundant synapseassociated proteins plays an important role in functional rehabilitation after ischemia (Mizutani et al. 2011). How these proteins regulate synaptic structure and signal transmission has attracted the attention of researchers. The impact of exercise training on these proteins and their expression in the recovery process of stroke are diverse. MAP2 The microtubule-associated protein 2 (MAP2) has been known as a filamentous, heat-stable, neuron-specific protein, which adheres to microtubules when prepared from mammalian brain extract by repeated assembly–disassembly of tubulin dimmers (Friedrich and Aszodi 1991). And the protein also has been considered as a cross-linker and

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adjustable spacer in dendritic architecture (Friedrich and Aszodi 1991). It is necessary in regulating microtubule networks in the axons and dendrites of neurons as well as the nucleation and stabilization of microtubules (Hirokawa et al. 1988). Moreover, MAP2 is also the anchorage of regulatory proteins such as protein kinases which may be important for signal transduction. MAP2 interacts with actin filaments, shown to be necessary for neurite outgrowth (Kim et al. 1979; Selden and Pollard 1983, 1986; Sattilaro 1986; Kalcheva et al. 1998) in a middle cerebral artery occlusion (MCAO) animal model and in an in vitro study. In its different phosphorylation states, MAP2 plays a critical role in the formation of axons, regeneration, and reconstruction of axons’ function (Drewes et al. 1998; Gundersen and Cook 1999) in response to different extracellular signals (Norden et al. 1991). Meanwhile, MAP2 is present during all stages of neuronal morphogenesis (Caceres et al. 1986). And the ability of MAP2 to interact with both microtubules and F-actin might be critical for neuronal morphogenesis processes, such as neurite initiation (Caceres et al. 1986; Bernhardt and Matus 1984; Caceres et al. 1992) and polarity. As a neuron-specific cytoskeletal protein, MAP2 was damaged by brain ischemic injury (Song et al. 2015). While a significant increase in MAP2 phosphorylation is observed during the first 3 days of the culture of hippocampal neurons, when dendrite arborization takes place (Diez-Guerra and Avila 1993). So increased levels of MAP2 should be connected with the recovery of synaptic structural damage. Increased levels of MAP2 were detected in the hippocampus with treadmill exercise (Ferreira et al. 2011). Consistently, the levels of MAP-2 in the hippocampus were also enhanced by voluntary and involuntary exercise training (Lin et al. 2015). BDNF Neurotrophic molecules regulate synaptic plasticity of the nervous system (Mattson 1988; Loers and Schachner 2007; Gottmann et al. 2009). Specifically, many researches demonstrated that brain-derived neurotrophic factor (BDNF) accelerates the axon genesis (Mattson and Partin 1999; Lipsky and Marini 2007), promotes poststroke plasticity in an in vivo study (Lipsky and Marini 2007; Binder and Scharfman 2004; Chen et al. 2005; Kim et al. 2005; Schabitz et al. 2007), and contributes to healthy brain function. Notably, neuronal survival and maintenance, neurogenesis, modulation of dendritic branching and dendritic spine morphology (Horch and Katz 2002; Tanaka et al. 2008), and development of neuronal connections are required for learning and memory (McAllister et al. 1995; Patterson et al. 1996). BDNF, through phosphorylation of its TrkB receptor, activates a neuron-specific protein,

controls the actin cytoskeleton in dendritic spines (Sala et al. 2001) and their regression (Xu et al. 2000), and promotes the actin polymerization (Bramham and Wells 2007). BDNF signaling plays a crucial role in the development of synapses by controlling the transport of PSD-95 (Yoshii and Constantine-Paton 2007), and its interaction with BDNF signaling has been implicated in diverse brain diseases (Tsai et al. 2012; Cao et al. 2013). Exercise may enhance synaptic plasticity in the hippocampus by increasing brain-derived neurotrophic factors (BDNFs) (Ploughman et al. 2005; Alomari et al. 2013). BDNF is upregulated by neuromuscular activity, including endurance exercise and functional rehabilitation, in intact (Klintsova et al. 2004) and ischemic animals contributing to improve the performance in cognitive/motor tasks (Kleim et al. 2003; Ploughman et al. 2007). Increase level of BDNF is detected in the hippocampus with treadmill exercise (Ferreira et al. 2011) and the increase of its mRNAs has also been widely reported after exercise (Berchtold et al. 2010; Neeper et al. 1996). Compared to a single training, BDNF expression is increased significantly in treadmill training combined with skill training on MCAO rats (Ploughman et al. 2007). In addition, some scholars put forward that early high-intensity exercise after brain ischemic injury inhibits the expression of BDNF and goes against the recovery of neural function (Griesbach et al. 2004; Branchi et al. 2006). These suggest that various expression levels of BDNF are affected by movement mode and intensity changes in the process of recovery after cerebral ischemia. CaMKII Calcium–calmodulin-dependent kinase II (CaMKII) is an abundant synaptic signaling molecule, whose concentration in neuronal tissue is at least 20-fold higher than in nonneuronal tissues, representing up to 1 % of brain protein (Schulman 1991; Schulman and Hanson 1993). CaMKII is essential for LTP, learning, and memory (Shonesy et al. 2014), and plays a prominent role in synaptic tagging and metaplasticity. Through its unique regulatory properties, CaMKII gets together with MAP2 and actin, and mediates synaptic transmission (Wu et al. 1992; Langnaese et al. 1996) in dendritic spines and PSD. Even more, CaMKII plays a structural role via direct interaction with actin filaments, thus coupling functional and structural plasticity in dendritic spines (Okamoto et al. 2009). In addition to its structural function, CaMKII may function as a ‘memory molecule’ since this enzyme acquires a calcium-independent capacity of phosphorylation upon activation by Ca? 2-calmodulin for a time longer than the duration of the activating calcium signal (Chakravarthy et al. 1999; Leonard et al. 1999). Increased CaMKII activity can cause

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changes in spine morphology, but aberrant CaMKII activity in the medial prefrontal cortex is associated with cognitive dysfunction (Yabuki et al. 2014). Additionally, there is an increase of CaMKII levels, and CaMKII activity, in the PSD following high-frequency tetanic stimulation (Lee et al. 2009; Strack et al. 1997) and ischemia (Meng et al. 2003). It has been reported that cerebral ischemia induces translocation of CaMKIIa which targets to and phosphorylates NR2B in hippocampus of rats (Aronowski et al. 2000), thus the translocation of CaMKIIa is related to synaptic dysfunction. Thus, the exact time window of increased activity and how this is terminated are still the matter of debate (Yabuki et al. 2014). The expression of CaMKII in skeletal muscle increases with endurance training (Ghosh et al. 2015) and aerobic exercise training (Kemi et al. 2007). But there are few studies about the expression of CaMKII in neurons. After a task-oriented training, CaMKII activity is increased for at least 30 min. This CaMKII activity and further activation of CaMKII may be regulated by changes in the expression of two endogenous CaMKII inhibitor proteins, CaMKII inhibitor Alpha and Beta, as they are upregulated early after training (Lucchesi et al. 2011). Spatial training leads to selective activation of CaMKII, which indicates that spatial training can preserve the cognitive function by CaMKII-dependent remodeling of dendritic plasticity (Jiang et al. 2015). Indeed, hippocampal LTP has been shown to be essentially dependent on CaMKII (Malenka et al. 1989; Otmakhov et al. 1997; Silva et al. 1992). GFAP Glial fibrillary acidic protein (GFAP) is the main intermediate filament protein in mature astrocytes and also important for astrocyte–neuronal interactions, and plays a vital role in modulating synaptic efficacy in the central nervous system (Eng et al. 2000). As a marker of reactive astrocytes during normal aging (Goss et al. 1991; Morgan et al. 1997), increase of GFAP expression may be a factor in impaired synaptic plasticity (Finch 2003). Some studies show that GFAP is involved in cell motility and migration; however, to what extent it contributes to normal physiological or pathological functions in different astrocyte subtypes is yet unknown (Lepekhin et al. 2001; Yoshida et al. 2007). Suppressed expression of GFAP is correlated with increased glutamine synthetase activity (Weir and Thomas 1984), whereas increased GFAP is correlated with a decrease in glutamine levels and in glutamate–glutamine conversion rates (Lieth et al. 1998). GFAP is suggested to be involved in the maintenance of normal CNS myelination (Gimenez et al. 2000; Liedtke et al. 1996). Astrocytes upregulate in 1 day following motor axon injury. And analogous responses occur in central termination territories

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of peripherally injured neuron (Middeldorp and Hol 2011). In addition to these neurodegenerative diseases, GFAP expression has also been reported to be altered in different neurological conditions including developmental, infectious and inflammatory, vascular, and mood disorders. High GFAP levels in the CSF in general have been seen in the context of acute CNS injury, such as brain infarction (Aurell et al. 1991). Additionally, they find evidence for a high susceptibility to cerebral ischemia in these mice, which implies an important role for astrocytes and GFAP in the progress of ischemic brain damage after focal cerebral ischemia with partial reperfusion (Nawashiro et al. 2000) and traumatic brain injury (Hausmann et al. 2000). Furthermore, ischemia induced a significant depression in hippocampal slices of GFAP-/- mice after high-frequency stimulation and paired pulse facilitation, whereas little difference was observed under normal conditions. There is evidence that treadmill exercise increases the level of GFAP in the hippocampus (Ferreira et al. 2011), the frontoparietal cortex, and dorsolateral striatum (Li et al. 2005) of exercised rats. Conversely, the previous study has found that the immunocontent of GFAP is increased in the ipsilateral sensorimotor cortex in all ischemic animals, but skilled and unskilled training do not alter the GFAP expression (Pagnussat et al. 2012). It has been evidenced that injury results in increased expression of GFAP protein in CNS (Ridet et al. 1997). This reactive astrocytic response after injury could form glial scar tissue and sometimes hinder axonal growth (Alonso and Privat 1993). On the other hand, reactive astrocytes can play a role in neural plasticity in intact animals (Sirevaag and Greenough 1991) or after cerebral ischemia and rehabilitation contributing toward the amelioration of functional impairment (Briones et al. 2006). Effect of Training on Molecular Organization of the Constituent of Postsynaptic Membrane Receptor N-methyl D-aspartate receptors (NMDARs) and a-amino-3hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) are key mediators of excitatory synaptic transmission in the brain. Both receptor types are glutamate-gated cation channels that convert a chemical signal (glutamate released from presynaptic terminals) to an electric signal (a membrane voltage change due to cation flow through the channels). Most NMDAR subtypes are unique in that their opening requires the coincidence of both presynaptic glutamate release and a strong postsynaptic membrane depolarization to relieve Mg2? block of the channel. NMDARs are permeable to Na?, K?, and Ca2? ions, the latter of which acts as a second messenger to modify synapses (Lynch et al. 1983). These receptor

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properties promote input specificity of Ca2?-dependent synaptic modifications by NMDARs. Tang et al. reported (Tang et al. 1999) that overexpression of NR2B (an NMDA subunit) in the hippocampus of mice was required for synaptic plasticity, and found that memories and cognition were all significantly enhanced. AMPARs, which are enriched in the postsynaptic membrane on dendritic spines, are highly dynamic, and shuttle in and out of synapses in an activity-dependent manner. Changes in their number, subunit composition, phosphorylation state, and accessory proteins can all regulate AMPARs, and thus modify synaptic strength and support cellular forms of learning. A tight regulation of NMDARs is also required in the exercise-induced facilitated memory processes with increased NMDAR/AMPAR levels. One mechanism of action can be that NMDARs activate CREB and set in motion the gene expression changes discussed above. These changes would then lead to morphological modifications at the synapse, including growth of new spines and increased AMPAR insertion. It is possible that these synaptic changes may represent the endpoint of many memory enhancers. Hence, targeting receptor expression may be a general approach to achieve memory enhancement. Furthermore, dysregulation of AMPAR plasticity has been implicated in various pathological states. Autophosphorylation at T286 permits calcium-independent signaling, phosphorylation of NMDARs and AMPARs alters channel conductance, and cytoskeletal rearrangements promote activity-induced modulation of spine morphology. In addition to activitydependent phosphorylation of AMPAR subunit GluR1 at S831 by activated CaMKII, AMPARs show activity-dependent dynamic changes in their subcellular distribution. This AMPAR trafficking has attracted special attention with regard to the ‘‘silent synapse’’ concept. Accumulating electrophysiological and morphological evidence indicates that synapses lacking AMPARs but containing functional NMDARs—thus postsynaptically ‘‘silent’’—can be ‘‘unsilenced’’ by the activity-induced appearance of AMPAR, thereby potentiating synaptic transmission (Sheng and Lee 2001). In MCAO rats, Tang found that the expression of AMPA receptor and its transport-related protein PICK1 was increased in the lesion periphery of ischemia after willed-movement training (Tang et al. 2007, 2013). Exercise increases total GluA2 subunit expression and induced alterations in GluA1 and GluA2 subunit of AMPAR expression in postsynaptic protein of basal ganglia (Kintz et al. 2013). There was an increased expression of AMPAtype glutamate receptor subunits (GluR1 and GluR2/3) after longer exercise periods, which showed that promoted plastic GluR changes were involved in exercise-induced plasticity processes (Real et al. 2010). Finally, treadmill exercise also altered the expression of GluR2 and GluR1,

which suggest that adaptive changes in GluR2 subunit expression may be important in modulating experiencedependent neuroplasticity of the injured basal ganglia (VanLeeuwen et al. 2010). Treadmill exercise can be able to promote distinct synaptic reorganization processes among the exercised groups. In general, the intermittent exercise regimen induced a higher expression of presynaptic proteins, whereas the continuous exercise regimen increased postsynaptic GluA1 and GluA2/3 receptors (Real et al. 2015). Treadmill exercise can also improve NMDA receptor expression in mice (Park et al. 2014). On the other hand, there is a decrease of AMPA receptor expression after a short period of continuous treadmill exercise (Real et al. 2010). Reports indicate that treadmill exercise suppressed neuronal apoptosis through enhancing NMDA receptor expression (Chung et al. 2014). Restored NMDA receptor in cerebral cortex of mice is involved in the beneficial effects of voluntary exercise on synaptic plasticity alterations (Revilla et al. 2014). NR1 receptor subunit protein expression is increased 87 % by physical exercise. Physical exercise delays motor neuron death and leads to an increase in the postnatal maturation rate of the motor units. Furthermore, exercise is capable of specifically enhancing the expression of the gene encoding the major activating subunit of the NMDA receptor in motor neurons, namely the NR2A subunit (Biondi et al. 2008). The overall content of NMDA subunits R1, R2A, and R2B were not altered in mice that had exercised; however, the phosphorylated NMDA subunits, phospho-NMDAR1 (150 %), and phospho-NMDAR2B (183 %) showed a strong increase because exercise increased the content of phosphorylated forms of NMDA receptors. Altogether, our results point to a modulation of glutamatergic synapses by exercise with likely implications in the exercise-induced mental health (Dietrich et al. 2005). Effect of Training on Persistent Forms of Synaptic Plasticity The efficiency of synaptic transmission undergoes plastic modification in response to changes in input activity. This phenomenon is most commonly referred to as synaptic plasticity and two paradigmatic examples of changes in synaptic strength are long-term depression (LTD) and longterm potentiation (LTP), which are induced in a variety of brain regions with diverse stimulation protocols (Malenka and Bear 2004) and provide cellular models for testing mechanisms of plasticity associated with memory formation. In the past two decades, there are a large number of studies on the mechanism of LTP. The enhancement of AMPAR-mediated synaptic transmission is the defining process of LTP (Luthi et al. 2004). It is also believed that the induction of LTP involves the synaptic activation of

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NMDA type of glutamate receptors, and the consequent increase in postsynaptic intracellular calcium concentration to lead to LTP. It has been recognized that mechanisms underlying the induction of LTP engage in the genetic program of neurons and de novo synthesis of proteins (Bozon et al. 2003). Previous studies have shown an increase in synapsin I immunoreactivity during LTP in rat hippocampus (Sato et al. 2000). However, LTD is often deemed to be associated with memory loss. Since electrophysiological changes of LTP in the function of neurones in the vicinity and remote from the primary stroke area has been demonstrated that ischemic injury can results in impaired LTP as well as synaptic dysfunction. In consideration of the neuroprotective effect of some drugs (Ding et al. 2012), which can ameliorate the impaired LTP induced by cerebral ischemia, exercise training has similar effects on synaptic plasticity, promoting the induction of LTP and reducing the propensity for LTD (Kumar et al. 2012). Exercise training improved the opening conductance level, time, and probability of NMDA receptor channels and accelerated the formation of learning-dependent LTP in the contralateral hippocampal CA3 area (Yu et al. 2013). Exercise also significantly increased the mean baseline EPSP and PS responses, and augmented PS-LTP in groups which imply an effect of exercise on mechanisms of synaptic plasticity (Miladi-Gorji et al. 2014). Other reports implied that voluntary exercise enhances neurogenesis and reduces the threshold for LTP in the dentate gyrus (DG) but not in other areas of the hippocampus (Farmer et al. 2004). Rats that underwent exercise training demonstrated enhanced expression of LTP in DG and enhanced object recognition learning (O’Callaghan et al. 2007). Prior moderate treadmill exercise also prevented the impaired basal synaptic transmission and LTP in the DG. In addition, exercise normalized the basal levels of memory and LTP-related signaling molecules including CaMKII and BDNF ut supra (Dao et al. 2015).

Conclusion It has been consistently shown that repeated training trials are associated with better memory. This method is employed during everyday learning, and is also known to have benefits for cognitive disorders. We have considered various effect aspects of exercise training on synaptic plasticity in light of changes in synaptic structure and synaptic transmission. To sum up, exercise training has a significant impact on the synaptic plasticity of ischemia animals. That is to say, after brain ischemic injury, proper exercise training can cause adaptive changes in the number of synapses, morphology of synapses, and strength of

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synaptic transmission. Behavioral methods for enhancing synaptic plasticity and reverse cognitive disorders are exciting avenues of research, and may be extremely useful in clinical practice with more basic knowledge of how best to implement their practice, as well as whether they can be even further augmented through pharmacological means. Moreover, how to implement individualized rehabilitation therapy with appropriate type of exercise training, startup time, exercise intensity and maintain time for cerebral ischemia object according to the injury severity will be the focus of future research. Acknowledgments This study was financially supported by grants from Graduate students independently innovative Foundation of Central South University (No. 2012zzts039).

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