Activity-Induced Notch Signaling in Neurons Requires Arc/Arg3.1 and Is Essential for Synaptic Plasticity in Hippocampal Networks

Institute for Cell Engineering, Neuroregeneration Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Neuron (Impact Factor: 15.05). 02/2011; 69(3):437-44. DOI: 10.1016/j.neuron.2011.01.004
Source: PubMed


Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation.

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    • "That such an activity could also regulate F-actin is significant because studies in mice show that F-actin up regulation is important for memory formation and triggers the translocation of cytoskeleton-associated protein Arc/Arg3.1 into synapses (Lamprecht, 2011; Liu et al., 2012). Interestingly, Arc/Arg3.1 is required for proteolytic processing of Notch and synaptic plasticity (Alberi et al., 2011), which is consistent with our perspective that the sequence of activation of non-canonical and canonical Notch signaling might be important for LTM formation. Constitutive over-expression of either one of these activities might interfere with LTM formation. "
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    ABSTRACT: Notch is a cell surface receptor that is well known to mediate inter-cellular communication during animal development. Data in the field indicate that it is also involved in the formation of long-term memory (LTM) in the fully developed adults and in memory loss upon neurodegeneration. Our studies in the model organism Drosophila reveal that a non-canonical Notch-protein kinase C activity that plays critical roles in embryonic development also regulates cyclic-AMP response element binding protein during LTM formation in adults. Here we present a perspective on how the various known features of Notch function relate to LTM formation and how they might interface with elements of Wingless/Wnt signaling in this process.
    Frontiers in Cellular Neuroscience 11/2013; 7:222. DOI:10.3389/fncel.2013.00222 · 4.29 Impact Factor
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    • "Immunoreactivity for the active form of Notch (NICD) was found increased both in the nucleus and perikaryon of motoneurons from SMNΔ7 mice, demonstrating an activation of Notch signaling in SMA motoneurons. A similar pattern of NICD distribution has been described in hippocampal neurons in response to activity; in these cells a parallel increase in Notch receptor expression was also reported [45]. In agreement with these findings, we also found an increase in Notch receptor expression in SMA motoneurons. "
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    ABSTRACT: Spinal muscular atrophy (SMA) is a neurodegenerative disease produced by low levels of Survival Motor Neuron (SMN) protein that affects alpha motoneurons in the spinal cord. Notch signaling is a cell-cell communication system well known as a master regulator of neural development, but also with important roles in the adult central nervous system. Aberrant Notch function is associated with several developmental neurological disorders; however, the potential implication of the Notch pathway in SMA pathogenesis has not been studied yet. We report here that SMN deficiency, induced in the astroglioma cell line U87MG after lentiviral transduction with a shSMN construct, was associated with an increase in the expression of the main components of Notch signaling pathway, namely its ligands, Jagged1 and Delta1, the Notch receptor and its active intracellular form (NICD). In the SMNΔ7 mouse model of SMA we also found increased astrocyte processes positive for Jagged1 and Delta1 in intimate contact with lumbar spinal cord motoneurons. In these motoneurons an increased Notch signaling was found, as denoted by increased NICD levels and reduced expression of the proneural gene neurogenin 3, whose transcription is negatively regulated by Notch. Together, these findings may be relevant to understand some pathologic attributes of SMA motoneurons.
    International Journal of Molecular Sciences 06/2013; 14(6):11424-37. DOI:10.3390/ijms140611424 · 2.86 Impact Factor
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    • "ETP-50772; No. of Pages 9 J.Y. Ljubimova et al. / Experimental and Toxicologic Pathology xxx (2013) xxx– xxx 5 with brain tissue alterations that could possibly lead to tumor development after short exposure (two weeks) and long exposure (10 months). Overexpression of activity-regulated cytoskeleton-associated gene Arc/Arg3.1 (Entrez Gene: 23237) related to synaptic plasticity and cognitive functions (Okuno, 2011; Alberi et al., 2011) was among the most prominent changes detected in rat brains after two weeks CP exposure (Fig. 1). "
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    ABSTRACT: Air pollution negatively impacts pulmonary, cardiovascular, and central nervous systems. Although its influence on brain cancer is unclear, toxic pollutants can cause blood-brain barrier disruption, enabling them to reach the brain and cause alterations leading to tumor development. By gene microarray analysis validated by quantitative RT-PCR and immunostaining we examined whether rat (n=104) inhalation exposure to air pollution particulate matter (PM) resulted in brain molecular changes similar to those associated with human brain tumors. Global brain gene expression was analyzed after exposure to PM (coarse, 2.5-10μm; fine, <2.5μm; or ultrafine, <0.15μm) and purified air for different times, short (0.5, 1, and 3 months) and chronic (10 months), for 5h per day, four days per week. Expression of select gene products was also studied in human brain (n=7) and in tumors (n=83). Arc/Arg3.1 and Rac1 genes, and their protein products were selected for further examination. Arc was elevated upon two-week to three-month exposure to coarse PM and declined after 10-month exposure. Rac1 was significantly elevated upon 10-month coarse PM exposure. On human brain tumor sections, Arc was expressed in benign meningiomas and low-grade gliomas but was much lower in high-grade tumors. Conversely, Rac1 was elevated in high-grade vs. low-grade gliomas. Arc is thus associated with early brain changes and low-grade tumors, whereas Rac1 is associated with long-term PM exposure and highly aggressive tumors. In summary, exposure to air PM leads to distinct changes in rodent brain gene expression similar to those observed in human brain tumors.
    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 05/2013; 65(7-8). DOI:10.1016/j.etp.2013.04.002 · 1.86 Impact Factor
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