Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus.

The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament α-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.

Non-canonical function of ADAM10 in presynaptic plasticity.

A Disintegrin And Metalloproteinase 10 (ADAM10) plays a pivotal role in shaping neuronal networks by orchestrating the activity of numerous membrane proteins through the shedding of their extracellular domains. Despite its significance in the brain, the specific cellular localization of ADAM10 remains not well understood due to a lack of appropriate tools. Here, using a specific ADAM10 antibody suitable for immunostainings, we observed that ADAM10 is localized to presynapses and especially enriched at presynaptic vesicles of mossy fiber (MF)-CA3 synapses in the hippocampus. These synapses undergo pronounced frequency facilitation of neurotransmitter release, a process that play critical roles in information transfer and neural computation. We demonstrate, that in conditional ADAM10 knockout mice the ability of MF synapses to undergo this type of synaptic plasticity is greatly reduced. The loss of facilitation depends on the cytosolic domain of ADAM10 and association with the calcium sensor synaptotagmin 7 rather than ADAM10's proteolytic activity. Our findings unveil a new role of ADAM10 in the regulation of synaptic vesicle exocytosis.

Regulation of microtubule detyrosination by Ca2+ and conventional calpains.

Detyrosination is a major post-translational modification of microtubules (MTs), which has significant impact on MT function in cell division, differentiation, growth, migration and intracellular trafficking. Detyrosination of α-tubulin occurs mostly via the recently identified complex of vasohibin 1 or 2 (VASH1 and VASH2, respectively) with small vasohibin binding protein (SVBP). However, there is still remaining detyrosinating activity in the absence of VASH1 and/or VASH2 and SVBP, and little is known about the regulation of detyrosination. Here, we found that intracellular Ca2+ is required for efficient MT detyrosination. Furthermore, we show that the Ca2+-dependent proteases calpains 1 and 2 (CAPN1 and CAPN2, respectively) regulate MT detyrosination in VASH1- and SVBP-overexpressing human embryonic kidney (HEK293T) cells. We identified new calpain cleavage sites in the N-terminal disordered region of VASH1. However, this cleavage did not affect the enzymatic activity of vasohibins. In conclusion, we suggest that the regulation of VASH1-mediated MT detyrosination by calpains could occur independently of vasohibin catalytic activity or via another yet unknown tubulin carboxypeptidase. Importantly, the Ca2+ dependency of calpains could allow a fine regulation of MT detyrosination. Thus, identifying the calpain-regulated pathway of MT detyrosination can be of major importance for basic and clinical research.

Comparative Analysis of Primary Ovarian Cancer Cells and Established Cell Lines as a New Tool for Studies on Ovarian Cancer Cell Complexity.

Primary cancer cells reflect the genetic background and phenotype of a tumor. Immortalized cells with higher proliferation activity have an advantage over primary cells. The aim of the study was to immortalize the primary ovarian cancer (OvCa) cells using the plasmid-carrying human telomerase reverse transcriptase (hTERT) gene and compare their phenotype and biological activity with the primary cells. The primary OvCa3 A and OvCa7 A cells were isolated from the ascitic fluid of two high-grade serous ovarian cancer patients and were characterized using immunocytochemical methods, flow cytometry, real-time RT-PCR, Western blot, metabolic activity, and migratory potential. Both immortalized ovarian cancer cell lines mirrored the phenotype of primary cancer cells, albeit with modifications. The OvCa3 A hTERT cells kept the mesenchymal stem cell phenotype of CD73/CD90/CD105-positivity and were CD133-negative, whereas the cell population of OvCa7 A hTERT lost CD73 expression, but almost 90% of cells expressed the CD133 characteristic for the CSCs phenotype. Immortalized OvCa cells differed in gene expression level with respect to Sox2 and Oct4, which was associated with stemness properties. The OvCa7 A hTERT cells showed higher metabolic and migratory activity and ALDH1 expression than the corresponding primary OvCa cells. Both primary and immortalized cell lines were able to form spheroids. The newly established unique immortalized cell line OvCa7 A hTERT, with the characteristic of a serous ovarian cancer malignancy feature, and with the accumulation of the p53, Pax8, and overexpression of the CD133 and CD44 molecules, may be a useful tool for research on therapeutic approaches, especially those targeting CSCs in ovarian cancer and in preclinical 2D and 3D models.

F-actin patches associated with glutamatergic synapses control positioning of dendritic lysosomes.

Organelle positioning within neurites is required for proper neuronal function. In dendrites, with their complex cytoskeletal organization, transport of organelles is guided by local specializations of the microtubule and actin cytoskeleton, and by coordinated activity of different motor proteins. Here, we focus on the actin cytoskeleton in the dendritic shaft and describe dense structures consisting of longitudinal and branched actin filaments. These actin patches are devoid of microtubules and are frequently located at the base of spines, or form an actin mesh around excitatory shaft synapses. Using lysosomes as an example, we demonstrate that the presence of actin patches has a strong impact on dendritic organelle transport, as lysosomes frequently stall at these locations. We provide mechanistic insights on this pausing behavior, demonstrating that actin patches form a physical barrier for kinesin-driven cargo. In addition, we identify myosin Va as an active tether which mediates long-term stalling. This correlation between the presence of actin meshes and halting of organelles could be a generalized principle by which synapses control organelle trafficking.

Osteogenic Potential of Human Dental Pulp Stem Cells (hDPSCs) Growing on Poly L-Lactide-Co-Caprolactone and Hyaluronic Acid (HYAFF-11TM) Scaffolds.

Bone tissue engineering using different scaffolds is a new therapeutic approach in regenerative medicine. This study explored the osteogenic potential of human dental pulp stem cells (hDPSCs) grown on a hydrolytically modified poly(L-lactide-co-caprolactone) (PLCL) electrospun scaffold and a non-woven hyaluronic acid (HYAFF-11™) mesh. The adhesion, immunophenotype, and osteogenic differentiation of hDPSCs seeded on PLCL and HYAFF-11™ scaffolds were analyzed. The results showed that PLCL and HYAFF-11™ scaffolds significantly supported hDPSCs adhesion; however, hDPSCs' adhesion rate was significantly higher on PLCL than on HYAFF-11™. SEM analysis confirmed good adhesion of hDPSCs on both scaffolds before and after osteogenesis. Alizarin red S staining showed mineral deposits on both scaffolds after hDPSCs osteogenesis. The mRNA levels of runt-related transcription factor 2 (Runx2), collagen type I (Coll-I), osterix (Osx), osteocalcin (Ocn), osteopontin (Opn), bone sialoprotein (Bsp), and dentin sialophosphoprotein (Dspp) gene expression and their proteins were higher in hDPSCs after osteogenic differentiation on both scaffolds compared to undifferentiated hDPSCs on PLCL and HYAFF-11™. These results showed that PLCL scaffolds provide a better environment that supports hDPSCs attachment and osteogenic differentiation than HYAFF-11™. The high mRNA of early osteogenic gene expression and mineral deposits observed after hDPSCs osteogenesis on a PLCL mat indicated its better impact on hDPSCs' osteogenic potential than that of HYAFF-11™, and hDPSC/PLCL constructs might be considered in the future as an innovative approach to bone defect repair.

Properties of scaffolds as carriers of mesenchymal stem cells for use in bone engineering.

Tissue engineering has become one of the most studied medical fields and appears to be promising for the regeneration of injured bone tissues. Even though the bone has self-remodeling properties, bone regeneration may be required in some cases. Current research concerns materials employed to develop biological scaffolds with improved features as well as complex preparation techniques. Several attempts have been made to achieve compatible and osteoconductive materials with good mechanical strength in order to provide structural support. The application of biomaterials and mesenchymal stem cells (MSCs) is a promising prospect for bone regeneration. Recently, various cells have been utilized alone or in combination with biomaterials to accelerate bone repair in vivo. However, the question of what cell source is the best for use in bone engineering remains open. This review focuses on studies that evaluated bone regeneration using biomaterials with MSCs. Different types of biomaterials for scaffold processing, ranging from natural and synthetic polymers to hybrid composites, are presented. These constructs demonstrated an enhanced ability to regenerate the bone in vivo using animal models. Additionally, future perspectives in tissue engineering, such as the MSC secretome, that is the conditioned medium (CM), and the extracellular vesicles (EVs), are also described in this review. This new approach has already shown promising results for bone tissue regeneration in experimental models.

Myosin V regulates synaptopodin clustering and localization in the dendrites of hippocampal neurons.

The spine apparatus (SA) is an endoplasmic reticulum-related organelle that is present in a subset of dendritic spines in cortical and pyramidal neurons, and plays an important role in Ca2+ homeostasis and dendritic spine plasticity. The protein synaptopodin is essential for the formation of the SA and is widely used as a maker for this organelle. However, it is still unclear which factors contribute to its localization at selected synapses, and how it triggers local SA formation. In this study, we characterized development, localization and mobility of synaptopodin clusters in hippocampal primary neurons, as well as the molecular dynamics within these clusters. Interestingly, synaptopodin at the shaft-associated clusters is less dynamic than at spinous clusters. We identify the actin-based motor proteins myosin V (herein referring to both the myosin Va and Vb forms) and VI as novel interaction partners of synaptopodin, and demonstrate that myosin V is important for the formation and/or maintenance of the SA. We found no evidence of active microtubule-based transport of synaptopodin. Instead, new clusters emerge inside spines, which we interpret as the SA being assembled on-site.

Sonic Hedgehog is a novel prognostic biomarker in patients with oral squamous cell carcinoma.

Recent studies revealed that Sonic Hedgehog (SHH) signaling pathway plays an important role in initiation and tumor progression in various malignancies, however, its role in oral squamous cell carcinoma (OSCC) remains unclear. The objective of this study was to investigate the prognostic significance of SHH expression in patients with OSCC in relation to p53 protein expression and human papillomavirus (HPV) presence. SHH, p53, HPV expression was analyzed in surgical specimens from 70 patients with primary OSCC by immunohistochemistry (IHC) and correlated with clinicopathological parameters. The presence of SHH, p53, HPV was found in 51/70 (72.9%), 32/70 (45.7%), 11/70 (15.7%) cases, respectively. No correlation between SHH, p53 overexpression, and HPV presence was found. SHH expression was associated with tumor stage (p=0.026). P53 immunoreactivity correlated with tumor grade (p=0.040). By Kaplan-Meier analysis, SHH expression was significantly associated with shorter overall survival (p=0.005). Multivariate cox regression analysis showed that SHH was an independent prognostic factor for overall survival (HR=2.93; 95% CI=1.40-6.13; p=0.004). Our findings revealed that the SHH signaling pathway contributes to the poor survival of patients with OSCC and should be considered as a new prognostic biomarker in patients with OSCC. Inhibition of the SHH pathway may be used as a new potential target in cancer therapy.

Dental Pulp Stem Cell-Derived Secretome and Its Regenerative Potential.

The therapeutic potential of the dental pulp stem (DSC) cell-derived secretome, consisting of various biomolecules, is undergoing intense research. Despite promising in vitro and in vivo studies, most DSC secretome-based therapies have not been implemented in human medicine because the paracrine effect of the bioactive factors secreted by human dental pulp stem cells (hDPSCs) and human exfoliated deciduous teeth (SHEDs) is not completely understood. In this review, we outline the current data on the hDPSC- and SHED-derived secretome as a potential candidate in the regeneration of bone, cartilage, and nerve tissue. Published reports demonstrate that the dental MSC-derived secretome/conditional medium may be effective in treating neurodegenerative diseases, neural injuries, cartilage defects, and repairing bone by regulating neuroprotective, anti-inflammatory, antiapoptotic, and angiogenic processes through secretome paracrine mechanisms. Dental MSC-secretomes, similarly to the bone marrow MSC-secretome activate molecular and cellular mechanisms, which determine the effectiveness of cell-free therapy. Many reports emphasize that dental MSC-derived secretomes have potential application in tissue-regenerating therapy due to their multidirectional paracrine effect observed in the therapy of many different injured tissues.

Posttranslational modification impact on the mechanism by which amyloid-ß induces synaptic dysfunction.

Oligomeric amyloid-ß (Aß) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aß have been identified, among which N-terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms. Here, we show that a prominent isoform, pyroglutamated Aß3(pE)-42, induces synaptic dysfunction to a similar extent like Aß1-42 but by clearly different mechanisms. In contrast to Aß1-42, Aß3(pE)-42 does not directly associate with synaptic membranes or the prion protein but is instead taken up by astrocytes and potently induces glial release of the proinflammatory cytokine TNFα. Moreover, Aß3(pE)-42-induced synaptic dysfunction is not related to NMDAR signalling and Aß3(pE)-42-induced impairment of synaptic plasticity cannot be rescued by D1-agonists. Collectively, the data point to a scenario where neuroinflammatory processes together with direct synaptotoxic effects are caused by posttranslational modification of soluble oligomeric Aß and contribute synergistically to the onset of synaptic dysfunction in AD.

In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15.

A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10. Cell-based overexpression experiments revealed that this binding affected the maturation process and surface expression of the protease. Our current study shows that Tspan15 is abundantly expressed in mouse brain, where it specifically interacts with endogenous ADAM10. Tspan15 knockout mice did not reveal an overt phenotype but showed a pronounced decrease of the active and mature form of ADAM10, an effect which augmented with aging. The decreased expression of active ADAM10 correlated with an age-dependent reduced shedding of neuronal (N)-cadherin and the cellular prion protein. APP α-secretase cleavage and the expression of Notch-dependent genes were not affected by the loss of Tspan15, which is consistent with the hypothesis that different TspanC8s cause ADAM10 to preferentially cleave particular substrates. Analyzing spine morphology revealed no obvious differences between Tspan15 knockout and wild-type mice. However, Tspan15 expression was elevated in brains of an Alzheimer's disease mouse model and of patients, suggesting that upregulation of Tspan15 expression reflects a cellular response in a disease state. In conclusion, our data show that Tspan15 and most likely also other members of the TspanC8 family are central modulators of ADAM10-mediated ectodomain shedding in vivo.

A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis.

Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.

[The role of cancer stem cells in progressive growth and resistance of ovarian cancer: true or fiction?]. / Udzial nowotworowych komórek macierzystych w progresywnym wzroscie i opornosci raka jajnika: prawda czy mit?

Growing evidence indicates that biological heterogeneity of ovarian cancer is associated with a small subpopulation of cancer cells existing within tumor tissue and defined as cancer stem cells (CSCs). This small group of ovarian cells possesses the capacity of self-renewal. Recent data revealed that progression, metastasis and relapse of ovarian cancers are related to the behavior of cancer stem cells. However, how ovarian CSCs maintain their migration properties is still unclear. The clinical relevance of CSCs has been supported by emerging evidence, showing that CSCs are resistant to conventional chemotherapy of ovarian cancer. Identification of biomarkers of ovarian cancer stem cells seems to be important for target therapy. Therapeutic strategies aimed at eliminating CSCs in ovarian cancers might extend disease survival and limit recurrence. This review will describe the current knowledge of ovarian CSCs biology and contribution of these cells to metastasis and chemoresistance of ovarian cancer as well as the possibility to use target therapy of ovarian CSCs.

The role of p53 protein and MMP-2 tumor/stromal cells expression on progressive growth of ovarian neoplasms.

The aim of our study was to evaluate p53 gene/protein status and MMP-2 expression in respect to ovarian tumors progress to define the role of these markers in the metastasis of ovarian carcinomas. MMP-2 and p53 alterations were evaluated on 80 malignant, 30 benign ovarian tumors, and 62 metastatic lesions by using HRM method for mutations in p53 gene and by using RT-PCR for mRNA MMP-2 level. Our data indicate that parallel expression of MMP-2 epithelial/stromal cells and p53 may enhance cells invasion and metastasis in ovarian carcinoma.

[Stem and progenitor cells in biostructure of blood vessel walls]. / Komórki macierzyste i progenitorowe w biostrukturze scian naczyn krwionosnych.

Development of vascular and hematopoietic systems during organogenesis occurs at the same time. During vasculogenesis, a small part of cells does not undergo complete differentiation but stays on this level, "anchored" in tissue structures described as stem cell niches. The presence of blood vessels within tissue stem cell niches is typical and led to identification of niches and ensures that they are functioning. The three-layer biostructure of vessel walls for artery and vein, tunica: intima, media and adventitia, for a long time was defined as a mechanical barrier between vessel light and the local tissue environment. Recent findings from vascular biology studies indicate that vessel walls are dynamic biostructures, which are equipped with stem and progenitor cells, described as vascular wall-resident stem cells/progenitor cells (VW-SC/PC). Distinct zones for vessel wall harbor heterogeneous subpopulations of VW-SC/PC, which are described as "subendothelial or vasculogenic zones". Recent evidence from in vitro and in vivo studies show that prenatal activity of stem and progenitor cells is not only limited to organogenesis but also exists in postnatal life, where it is responsible for vessel wall homeostasis, remodeling and regeneration. It is believed that VW-SC/PC could be engaged in progression of vascular disorders and development of neointima. We would like to summarize current knowledge about mesenchymal and progenitor stem cell phenotype with special attention to distribution and biological properties of VW-SC/PC in biostructures of intima, media and adventitia niches. It is postulated that in the near future, niches for VW-SC/PC could be a good source of stem and progenitor cells, especially in the context of vessel tissue bioengineering as a new alternative to traditional revascularization therapies.

The Role of Hedgehog Signaling Pathway in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading malignancy worldwide, with a poor prognosis and limited treatment options. Molecularly targeted therapies for HNSCC are still lacking. However, recent reports provide novel insights about many molecular alterations in HNSCC that may be useful in future therapies. Therefore, it is necessary to identify new biomarkers that may provide a better prediction of the disease and promising targets for personalized therapy. The poor response of HNSCC to therapy is attributed to a small population of tumor cells called cancer stem cells (CSCs). Growing evidence indicates that the Hedgehog (HH) signaling pathway plays a crucial role in the development and maintenance of head and neck tissues. The HH pathway is normally involved in embryogenesis, stem cell renewal, and tissue regeneration. However, abnormal activation of the HH pathway is also associated with carcinogenesis and CSC regulation. Overactivation of the HH pathway was observed in several tumors, including basal cell carcinoma, that are successfully treated with HH inhibitors. However, clinical studies about HH pathways in HNSCC are still rare. In this review, we summarize the current knowledge and recent advances regarding the HH pathway in HNSCC and discuss its possible implications for prognosis and future therapy.

Prognostic Value of WNT1, NOTCH1, PDGFRß, and CXCR4 in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: The biological behaviour of oral squamous cell carcinoma (OSCC) might be an effect of aberrant activation of several signalling pathways, like WNT and NOTCH pathways. The purpose of this study was to investigate the prognostic significance of WNT1 and NOTCH1 in patients with OSCC in relation to pro-angiogenic factors (PDGFRß, CXCR4). MATERIALS AND METHODS: Immunohistochemistry was performed in 60 OSCC tissue samples to compare WNT1, NOTCH1, PDGFRß, and CXCR4 expression and correlate it with clinicopathological parameters. RESULTS: Immunoreactivity of WNT1, NOTCH1, PDGFRß, and CXCR4 was found in 51.7%, 25.0%, 63.3%, and 70.0% of the patients, respectively. WNT1 expression was positively correlated with NOTCH1 (r=0.269, p=0.037) and CXCR4 (r=0.268, p=0.038). Positive correlation was observed also between NOTCH1 and CXCR4 (r=0.493, p<0.001). WNT1 and PDGFRß expression was significantly associated with shorter overall survival (p=0.042, p=0.033, respectively). Multivariate Cox regression model revealed that WNT1 and CXCR4 were independent prognostic factors (p=0.009, p=0.021, respectively). CONCLUSION: WNT1 and NOTCH1 expression is associated with CXCR4 expression in OSCC, suggesting that WNT and NOTCH pathways are important in oral tumour angiogenesis. Moreover, WNT1 and CXCR4 could serve as independent prognostic factors for patients with OSCC.

A Jacob/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death.

Jacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-ß and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimer's disease pathology and the absence of Jacob protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. nsmf is the gene that encodes for the Jacob protein. Here we show that organotypic hippocampal slices from wild-type and nsmf-/- mice display similar degrees of degeneration when exposed to either oxygen glucose deprivation or 50 µM NMDAto induce excitotoxicity. This lack of neuroprotection indicates that JaCS is mainly relevant in conditions of low level chronic extrasynaptic NMDAR activation that results in cellular degeneration induced by alterations in gene transcription.

Long-distance signaling from synapse to nucleus via protein messengers.

The communication between synapses and the cell nucleus has attracted considerable interest for many years. This interest is largely fueled by the idea that synapse-to-nucleus signaling might specifically induce the expression of genes that make long-term memory "stick." However, despite many years of research, it is still essentially unclear how synaptic signals are conveyed to the nucleus, and it remains to a large degree enigmatic how activity-induced gene expression feeds back to synaptic function. In this chapter, we will focus on the activity-dependent synapto-nuclear trafficking of protein messengers and discuss the underlying mechanisms of their retrograde transport and their supposed functional role in neuronal plasticity.