Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice

Lu, Xin-Jiang; Chen, X.-Q.; Weng, Jian; Zhang, H.-Y.; Pak, Daniel T.S.; Luo, Jianhong; Du, Ji-Zeng

doi:10.1016/j.neuroscience.2009.05.011

Cited by 28 publications

(24 citation statements)

References 42 publications

(56 reference statements)

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“…These studies are in agreement with previous studies, which showed that both proteins are involved in morphological rearrangements in neurons (Murai et al, 2003;Pak et al, 2001). Recent research has implicated SPAR1 also in NMDA-induced excitotoxicity and neurodegeneration (Wu et al, 2007), as well as in synaptic plasticity following hypoxia (Lu et al, 2009). The pathophysiological relevance of synaptic SPAR expression, however, is just beginning to emerge.…”

Section: ;supporting

confidence: 91%

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RapGAPs in brain: multipurpose players in neuronal Rap signalling

Spilker

Kreutz

2010

Eur J of Neuroscience

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Small Rap guanosine-tri-phosphate (GTP)ases are crucially involved in many cellular processes, including cell proliferation, differentiation, survival, adhesion and movement. In line, it has been shown that Rap signalling is involved in various aspects of neuronal differentiation, like the establishment of neuronal polarity or axonal growth cone movement. Rap GTPases can be activated by a wide variety of external stimuli, and this is mediated by specific guanine nucleotide exchange factors (RapGEFs). Inactivation of RapGTP can be achieved with the aid of specific GTPase-activating proteins (RapGAPs). In the brain, the most prominent RapGAPs are Rap1GAP and those of the spine-associated RapGAP (SPAR) family. This latter family consists of three members (SPAR1-3), from which two of them, namely SPAR1 and 2, have been investigated in more detail. As such, the localization of RapGAPs is crucially important in regulating Rap signalling at various sites in the cell and, for both SPAR1 and 2, enrichment at synaptic sites has been demonstrated. In recent years particularly the role of SPAR1 in shaping dendritic spine morphology has attracted considerable interest. In this review we will summarize the described actions of different RapGAPs expressed in the brain, and we will focus in particular on the SPAR family members.

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Section: ;supporting

confidence: 91%

“…Recent research has implicated SPAR1 also in NMDA‐induced excitotoxicity and neurodegeneration (Wu et al. , 2007), as well as in synaptic plasticity following hypoxia (Lu et al. , 2009).…”

Section: Structural Plasticity At Dendritic Spines Of Pyramidal Neuromentioning

confidence: 99%

RapGAPs in brain: multipurpose players in neuronal Rap signalling

Spilker

Kreutz

2010

Eur J of Neuroscience

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“…In recent studies, we showed that a short (5 min) neonatal hypoxia in rats can activate endogenous brain neurogenesis that secondarily gives rise to a significant functional gain [9], [12]. In good agreement, Lu et al [33] reported that postnatal exposure to mild intermittent hypoxia (16% O2, 4 h/day for 4 weeks) enhances spatial learning and memory in developing mice. However, whereas cell mechanisms involved remain poorly understood, no information was available on the long-term consequences on the aging brain of the surnumerary neurons produced in early life.…”

Section: Discussionsupporting

confidence: 72%

Non-Injurious Neonatal Hypoxia Confers Resistance to Brain Senescence in Aged Male Rats

et al. 2012

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Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal “conditioning-like” hypoxia (100% N2, 5 min) on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP) kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.

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“…The signaling pathways that link glutamate receptor and PSD‐95 to the postsynaptic actin cytoskeleton is the Spine‐associated Rap GTPase activating protein (SPAR). SPAR promotes actin polymerization by inhibiting Rap, a small GTPase protein, resulting in spine enlargement and enhanced stability of the spine (Hall, 1992; Jeon et al, 2007; Lu et al, 2009; Matus, 2000; Tada and Sheng, 2006). The increase in the amount of PSD‐95 and SPAR has been reported to be associated with the increase of NR2A‐containing NMDA receptor and the maturity of dendritic spine (Petralia et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the reduction in the amount of NR2B‐containing NMDA receptors, by disrupting the NR2B/PSD‐95 complex, is accompanied by a dramatic reduction in the induction of long‐term potentiation (LTP) (Gardoni et al, 2009). While SPAR antisense‐treated mice exhibit impaired acquisition of the Morris water maze navigating task, as well as impairment in memory retention of probe trails following training, there is a reduction in the hippocampal LTP without any alterations of the basal synaptic transmission (Lu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Prenatal stress increased Snk Polo‐like kinase 2, SCF β‐TrCP ubiquitin ligase and ubiquitination of SPAR in the hippocampus of the offspring at adulthood

Chutabhakdikul

Surakul

2013

Intl J of Devlp Neuroscience

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Exposure to excessive glucocorticoids during fetal development period contributes to later life psychopathology. Prenatal stress decreases dendritic spine density and impair LTP in the hippocampus of rat pups, however, the mechanisms regulating these changes are still unclear. Glutamate receptors are localized in the postsynaptic density. PSD-95 is a postsynaptic scaffolding protein that plays a role in synaptic maturation and regulation of the synaptic strength and plasticity. PSD-95 interacts with other proteins to form the protein networks that promote dendritic spine formation. The present study investigated the effect of prenatal stress on the levels of scaffolding proteins of NMDA receptor in the hippocampus in order to explain how prenatal stress alters the amount of NMDA receptor in the pups' brain. Pregnant rats were randomly assigned to either the prenatal stress (PS) or the control group (C). The pregnant rats in the PS group were restrained in a plexiglas restrainer for 4h/day during the GD 14-21. Control rats were left undisturbed for the duration of their pregnancies. The amount of PSD-95, SPAR, NR2A and NR2B, as well as the levels of Snk Polo-like kinase 2 and the SCF β-TrCP ubiquitin ligase were measured in the hippocampus of the offspring. The results show that prenatal stress induces a reduction in the amount of NR2B and NR2A subunits in the hippocampus of rat pups, parallel to the decrease in PSD-95 and SPAR at P40 and P60. Moreover, prenatal stress increases Snk and β-TrCP in the hippocampus of rat pups, and the timing correlates with the decrease of SPAR and PSD-95. Prenatal stress also induces a significantly increases in the level of ubiquitinated SPAR in the hippocampus of rat pups at adulthood. The results suggest that degradation of SPAR via UPS system may contribute to the loss of PSD-95 and NMDA receptor subunits in the hippocampus of rat pups at adulthood. In conclusion, the present work demonstrates that the developing brain is critically influenced by glucocorticoids, especially during pre- and early postnatal period, which can have long-term effects on brain development. In addition, an involvement of the UPS system in the prenatal stress model has led to a greater understanding of the effects of prenatal stress later on in life.

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Hippocampal spine-associated Rap-specific GTPase-activating protein induces enhancement of learning and memory in postnatally hypoxia-exposed mice

Cited by 28 publications

References 42 publications

RapGAPs in brain: multipurpose players in neuronal Rap signalling

RapGAPs in brain: multipurpose players in neuronal Rap signalling

Non-Injurious Neonatal Hypoxia Confers Resistance to Brain Senescence in Aged Male Rats

Prenatal stress increased Snk Polo‐like kinase 2, SCF β‐TrCP ubiquitin ligase and ubiquitination of SPAR in the hippocampus of the offspring at adulthood

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