Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity

Lochner, Janis E.; Spangler, Edward L.; Chavarha, Mariya; Jacobs, C.; McAllister, Kathryn A.L.; Schuttner, L.C.; Scalettar, Bethe A.

doi:10.1002/dneu.20650

Cited by 34 publications

(29 citation statements)

References 63 publications

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“…No changes were observed in the levels of full-length reelin or its fragments in the adult cortex, hippocampus, and cerebellum. The lack of obvious changes in reelin processing under basal conditions is consistent with a requirement of high levels of synaptic activity to drive the release and activation of tPA (Lochner et al, 2006; Lochner et al, 2008). Notwithstanding, we did still observe that the reelin N-R2 (370 kDa) and N-R6 (180 kDa) fragments were expressed in all tested regions, implying that other proteases expressed in the adult brain are responsible for reelin processing under basal conditions.…”

Section: Discussionsupporting

confidence: 70%

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

Trotter

Lussier

et al. 2014

Neuroscience

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The secreted glycoprotein reelin plays an indispensable role in neuronal migration during development and in regulating adult synaptic functions. The upstream mechanisms responsible for initiating and regulating the duration and magnitude of reelin signaling are largely unknown. Here we report that reelin is cleaved between EGF-like repeats 6–7 (R6–7) by tissue plasminogen activator (tPA) under cell-free conditions. No changes were detected in the level of reelin and its fragments in the brains of tPA knockouts, implying that other unknown proteases are responsible for generating reelin fragments found constitutively in the adult brain. Induction of NMDAR-independent long-term potentiation with the potassium channel blocker tetraethylammonium chloride (TEA-Cl) led to a specific up-regulation of reelin processing at R6–7 in wild-type mice. In contrast, no changes in reelin expression and processing were observed in tPA knockouts following TEA-Cl treatment. These results demonstrate that synaptic potentiation results in tPA-dependent reelin processing and suggest that extracellular proteolysis of reelin may regulate reelin signaling in the adult brain.

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Section: Discussionsupporting

confidence: 70%

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

Trotter

Lussier

et al. 2014

Neuroscience

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“…In hippocampal neurons, tissue plaminogen activator (tPA), plasmin and proBDNF are co-packaged in dense core vesicles (Lochner et al, 2008), and it has been postulated that plasmin cleaves proBDNF to form a pool of postsynaptic mature BDNF to stabilize LTP (Pang et al, 2004; Pang and Lu, 2004). Using fluorogenic probes, local conversion of proBDNF to mature BDNF has been detected near axonal processes (Je et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

proBDNF Negatively Regulates Neuronal Remodeling, Synaptic Transmission, and Synaptic Plasticity in Hippocampus

et al. 2014

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Summary Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF which binds p75NTR. In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knock-in mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR. Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission and plasticity, effects that are distinct from mature BDNF.

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“…In the absence of tPA, proBDNF is uncleaved and binds with high affinity to p75 NTR , resulting in reduced synaptogenesis, withdrawal of dendritic spines and neuronal apoptosis15. Thus tPA can serve to control which effect of BDNF is predominant17.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of p75 Neurotrophin Receptor Attenuates Isoflurane-mediated Neuronal Apoptosis in the Neonatal Central Nervous System

et al. 2009

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Background Exposure to anesthetics during synaptogenesis results in apoptosis and subsequent cognitive dysfunction in adulthood. Probrain derived neurotrophic factor (proBDNF) is involved in synaptogenesis and can induce neuronal apoptosis via p75 neurotrophic receptors (p75NTR). proBDNF is cleaved into mature BDNF (mBDNF) by plasmin, a protease converted from plasminogen by tPA that is released with neuronal activity; mBDNF supports survival and stabilizes synapses through TrkB receptors. We hypothesized that anesthetics suppresses tPA release from neurons, enhances p75NTR signaling, reduces synapses resulting in apoptosis. Methods Primary neurons (DIV5) and postnatal day 5-7 (PND5-7) mice were exposed to isoflurane (1.4%, 4 h) in 5% CO2, 95% air. Apoptosis was assessed by cleaved caspase-3 (Cl-Csp3) immunoblot and immunofluorescence microscopy. Dendritic spine changes were evaluated with the neuronal spine marker, drebrin. Changes in synapses in PND5-7 mouse hippocampi were assessed by electron microscopy. Primary neurons were exposed to tPA, plasmin, or pharmacologic inhibitors of p75NTR (Fc-p75NTR or TAT-Pep5) 15 min prior to isoflurane. TAT-Pep5 was administered by intraperitoneal injection to PND5-7 mice 15 min prior to isoflurane. Results Exposure of neurons in vitro (DIV5) to isoflurane decreased tPA in the culture medium, reduced drebrin expression (marker of dendritic filopodial spines) and enhanced Cl-Csp3. tPA, plasmin or TAT-Pep5 stabilized dendritic filopodial spines and decreased Cl-Csp3 in neurons. TAT-Pep5 blocked isoflurane-mediated increase in Cl-Csp3 and reduced synapses in PND5-7 mouse hippocampi. Conclusion tPA, plasmin, or p75NTR inhibition blocked isoflurane-mediated reduction in dendritic filopodial spines and neuronal apoptosis in vitro. Isoflurane reduced synapses and enhanced Cl-Csp3 in the hippocampus of PND5-7 mice, the latter effect being mitigated by p75NTR inhibition in vivo. These data support the hypothesis that isoflurane neurotoxicity in the developing rodent brain is mediated by reduced synaptic tPA release and enhanced proBDNF/p75NTR-mediated apoptosis.

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Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity

Cited by 34 publications

References 63 publications

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

proBDNF Negatively Regulates Neuronal Remodeling, Synaptic Transmission, and Synaptic Plasticity in Hippocampus

Inhibition of p75 Neurotrophin Receptor Attenuates Isoflurane-mediated Neuronal Apoptosis in the Neonatal Central Nervous System

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