Post-synaptic Release of the Neuronal Tissue-Type Plasminogen Activator (tPA)

Lenoir, Sophie; Varangot, Alexandre; Lebouvier, Laurent; Galli, Thierry; Hommet, Yannick; Vivien, Denis

doi:10.3389/fncel.2019.00164

Cited by 13 publications

(11 citation statements)

References 68 publications

(90 reference statements)

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“…Since neuroserpin expression is at most during the first postnatal week (Krueger et al, 1997 ), we chose the P0 time point for this analysis ( Supplementary Figure 1 ). We examined the somatosensory cortex of mice previously in utero electroporated at E14 with a plasmid encoding for green fluorescence protein (GFP) under the control of the tPA promoter (Lenoir et al, 2019 ), resulting in a strong green fluorescence in tPA-expressing cells. We observed expression of both neuroserpin and tPA-GFP throughout all layers of the cerebral cortex.…”

Section: Resultsmentioning

confidence: 99%

Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

et al. 2021

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Neuroserpin is a serine protease inhibitor that regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin is strongly expressed during nervous system development as well as during adulthood, when it is predominantly found in regions eliciting synaptic plasticity. In the hippocampus, neuroserpin regulates developmental neurogenesis, synaptic maturation and in adult mice it modulates synaptic plasticity and controls cognitive and social behavior. High expression levels of neuroserpin in the neocortex starting from prenatal stage and persisting during adulthood suggest an important role for the serpin in the formation of this brain region and in the maintenance of cortical functions. In order to uncover neuroserpin function in the murine neocortex, in this work we performed a comprehensive investigation of its expression pattern during development and in the adulthood. Moreover, we assessed the role of neuroserpin in cortex formation by comparing cortical lamination and neuronal maturation between neuroserpin-deficient and control mice. Finally, we evaluated a possible regulatory role of neuroserpin at cortical synapses in neuroserpin-deficient mice. We observed that neuroserpin is expressed starting from the beginning of corticogenesis until adulthood throughout the neocortex in several classes of glutamatergic projection neurons and GABA-ergic interneurons. However, in the absence of neuroserpin we did not detect any alteration either in cortical layer formation, or in neuronal soma size and dendritic length. Furthermore, no significant quantitative changes were observed in the proteome of cortical synapses upon neuroserpin deficiency. We conclude that, although strongly expressed in the neocortex, absence of neuroserpin does not lead to gross developmental abnormalities, and does not perturb the composition of the cortical synaptic proteome.

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Section: Resultsmentioning

confidence: 99%

Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

et al. 2021

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“…It converts plasminogen to plasmin, which in turn not only degrades ECM but also activates metalloproteases, chemokines, and neurotrophic factors, such as BDNF. tPA is released by both axons and dendrites through exosomal vesicles, with axonal release being activity-dependent (for review, see Lenoir et al, 2019 ). Astrocytes also regulate tPA levels, possibly by expressing tPA, but also by recycling the tPA secreted by neurons in the synaptic cleft so that it can then bind to various receptors and act as a neuromodulator (Casse et al, 2012 ).…”

Section: Non-cell-autonomous Factors From Local Cells For Short-range...mentioning

confidence: 99%

Non-Cell-Autonomous Factors Implicated in Parvalbumin Interneuron Maturation and Critical Periods

Gibel-Russo

Benacom

Nardo

2022

Front. Neural Circuits

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From birth to adolescence, the brain adapts to its environmental stimuli through structural and functional remodeling of neural circuits during critical periods of heightened plasticity. They occur across modalities for proper sensory, motor, linguistic, and cognitive development. If they are disrupted by early-life adverse experiences or genetic deficiencies, lasting consequences include behavioral changes, physiological and cognitive deficits, or psychiatric illness. Critical period timing is orchestrated not only by appropriate neural activity but also by a multitude of signals that participate in the maturation of fast-spiking parvalbumin interneurons and the consolidation of neural circuits. In this review, we describe the various signaling factors that initiate critical period onset, such as BDNF, SPARCL1, or OTX2, which originate either from local neurons or glial cells or from extracortical sources such as the choroid plexus. Critical period closure is established by signals that modulate extracellular matrix and myelination, while timing and plasticity can also be influenced by circadian rhythms and by hormones and corticosteroids that affect brain oxidative stress levels or immune response. Molecular outcomes include lasting epigenetic changes which themselves can be considered signals that shape downstream cross-modal critical periods. Comprehensive knowledge of how these signals and signaling factors interplay to influence neural mechanisms will help provide an inclusive perspective on the effects of early adversity and developmental defects that permanently change perception and behavior.

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“…Membrane depolarization induces the rapid release of tPA from cerebral cortical neurons, which modulates neuronal plasticity, learning, stress-induced anxiety, and visual cortex plasticity [55] . tPA and uPA activities have been localized to well-defined areas of the brain [56][57][58][59] and shown to participate in intracellular signaling that is independent of plasminogen activation (see below). tPA is the principal plasmin activator in the CNS with PAI-1 regulating its activity primarily in the extracellular space.…”

Section: Pas In the Cnsmentioning

confidence: 99%

Review of evidence implicating the plasminogen activator system in blood-brain barrier dysfunction associated with Alzheimer’s disease

Tang¹,

Gorin²,

Lein³

2022

AND

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Elucidating the pathogenic mechanisms of Alzheimer’s disease (AD) to identify therapeutic targets has been the focus of many decades of research. While deposition of extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated tau have historically been the two characteristic hallmarks of AD pathology, therapeutic strategies targeting these proteinopathies have not been successful in the clinics. Neuroinflammation has been gaining more attention as a therapeutic target because increasing evidence implicates neuroinflammation as a key factor in the early onset of AD disease progression. The peripheral immune response has emerged as an important contributor to the chronic neuroinflammation associated with AD pathophysiology. In this context, the plasminogen activator system (PAS), also referred to as the vasculature’s fibrinolytic system, is emerging as a potential factor in AD pathogenesis. Evolving evidence suggests that the PAS plays a role in linking chronic peripheral inflammatory conditions to neuroinflammation in the brain. While the PAS is better known for its peripheral functions, components of the PAS are expressed in the brain and have been demonstrated to alter neuroinflammation and blood-brain barrier (BBB) permeation. Here, we review plasmin-dependent and -independent mechanisms by which the PAS modulates the BBB in AD pathogenesis and discuss therapeutic implications of these observations.

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Post-synaptic Release of the Neuronal Tissue-Type Plasminogen Activator (tPA)

Cited by 13 publications

References 68 publications

Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

Non-Cell-Autonomous Factors Implicated in Parvalbumin Interneuron Maturation and Critical Periods

Review of evidence implicating the plasminogen activator system in blood-brain barrier dysfunction associated with Alzheimer’s disease

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