Caspase activity is essential for long‐term potentiation

Gulyaeva, N. V.; Kudryashov, I. E.; Kudryashova, I. V.

doi:10.1002/jnr.10730

Cited by 60 publications

(42 citation statements)

References 121 publications

(130 reference statements)

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“…In vitro and in vivo studies show that caspase-3 contributes not only to the regulation of neuronal morphology and cell migration, but its cleavage occurs also in mature neurons during long term potentiation of synaptic activity: caspase-3 inhibitors block long term potentiation, memory and learning (53)(54)(55). Long term potentiation, memory and learning are also strongly impaired in NCAM-deficient mice (56).…”

Section: Discussionmentioning

confidence: 99%

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Westphal

Sytnyk

Schachner

et al. 2010

Journal of Biological Chemistry

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Changes in neuronal morphology underlying neuronal differentiation depend on rapid and sustained cytoskeleton rearrangements in the growing neurites. Whereas cell adhesion molecules are well established as regulators of neuronal differentiation, less is known about the signaling mechanisms by which they influence the cytoskeleton. Here we show that the neural cell adhesion molecule (NCAM) associates with the active form of caspase-8 and that clustering of NCAM at the neuronal cell surface leads to activation of caspase-8 and -3 followed by the cleavage of the sub-membranous brain spectrin meshwork, but not of the actin or tubulin cytoskeleton. Inhibitors of caspase-8 and -3 specifically block the NCAM-dependent spectrin cleavage and abolish NCAM-dependent neurite outgrowth. NCAM-dependent rearrangements of the membrane associated spectrin meshwork via caspase-8 dependent caspase-3 activation are thus indispensable for NCAM-mediated neurite outgrowth.The establishment and maintenance of neuronal morphology are essential for brain development and functioning. The neural cell adhesion molecule (NCAM) 2 plays a prominent role in these processes by being involved in regulation of neuronal migration and differentiation as well as synaptogenesis in the developing nervous system and synaptic plasticity in the adult (1-4). NCAM is a member of the immunoglobulin superfamily of adhesion molecules and contains five immunoglobulin and two fibronectin-like type III domains within its extracellular part. In developing neurons, NCAM is highly expressed in two transmembrane isoforms with molecular weights of 140 kDa (NCAM140) and, to a lower extent, 180 kDa (NCAM180), which are generated via alternative splicing of the ncam1 gene. The extracellular portion of NCAM interacts with multiple binding partners on adjacent cells and in the extracellular matrix, including adhesion molecules, such as prion protein (PrP), L1, and NCAM itself (5, 6), growth factor receptors, such as FGFR and GFR␣ (7,8), and other receptors, such as receptor-type protein phosphatase ␤ or its secreted forms (9).Clustering of NCAM at the cell surface by its ligands promotes neurite outgrowth by inducing intracellular signaling cascades, initiated by the association of the intracellular domain of NCAM with and consequent activation of kinases and phosphatases, including CaMKII␣, PKC, and RPTP␣ (10 -12). Palmitoylation of the intracellular domain of NCAM (13) and association of NCAM with the cellular form of prion protein (PrP) (5) promote redistribution of NCAM and associated signaling molecules to lipid rafts where they activate downstream signal transducing proteins including fyn kinase and GAP43 (10,12,14,15).The cytoskeleton plays an important role in NCAM-dependent signaling, and clustering of NCAM at the cell surface induces formation of the spectrin-based cytoskeleton enriched in microdomains (3). However, little is known on how NCAM signaling is coordinated with the cytoskeleton reorganization including not only its polymerization but also local remode...

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Section: Discussionmentioning

confidence: 99%

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Westphal

Sytnyk

Schachner

et al. 2010

Journal of Biological Chemistry

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“…Blockade of postsynaptic calcium signaling prevented dendritic beading following HFS, but because calcium is crucial for long-term plasticity (45), this did not improve synaptic function in cPAF-exposed slices ( Figure 6). Likewise, caspase activity has been shown to be required for hippocampal LTP (46), and its inhibition prevented beading but failed to restore LTP. PAF-R antagonism, which inhibits LTP in some in vitro models but not in others (28,29,47), can impair hippocampal learning in vivo (31) and resulted in diminished LTP in our experiments; it thus may face similar limitations as a therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor

Bellizzi¹

2005

Journal of Clinical Investigation

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Neurologic impairment in HIV-1-associated dementia (HAD) and other neuroinflammatory diseases correlates with injury to dendrites and synapses, but how such injury occurs is not known. We hypothesized that neuroinflammation makes dendrites susceptible to excitotoxic injury following synaptic activity. We report that platelet-activating factor, an inflammatory phospholipid that mediates synaptic plasticity and neurotoxicity and is dramatically elevated in the brain during HAD, promotes dendrite injury following elevated synaptic activity and can replicate HIV-1-associated dendritic pathology. In hippocampal slices exposed to a stable platelet-activating factor analogue, tetanic stimulation that normally induces long-term synaptic potentiation instead promoted development of calcium-and caspase-dependent dendritic beading. Chemical preconditioning with diazoxide, a mitochondrial ATP-sensitive potassium channel agonist, prevented dendritic beading and restored long-term potentiation. In contrast to models invoking excessive glutamate release, these results suggest that physiologic synaptic activity may trigger excitotoxic dendritic injury during chronic neuroinflammation. Furthermore, preconditioning may represent a novel therapeutic strategy for preventing excitotoxic injury while preserving physiologic plasticity.

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“…At the electrophysiological level, Gulyaeva et al 41 showed that caspase-3 activity is required for long-term potentiation (LTP) in the CA1 region of rat hippocampus. The authors did not identify the precise molecular mechanism of caspase-3 involvement in LTP, although they do support the concept of the role of caspase-3 in synaptic plasticity.…”

Section: Caspase-3 and Neuroplasticitymentioning

confidence: 99%

Neuronal caspase-3 signaling: not only cell death

2009

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Caspases are a family of cysteinyl aspartate-specific proteases that are highly conserved in multicellular organisms and function as central regulators of apoptosis. A member of this family, caspase-3, has been identified as a key mediator of apoptosis in neuronal cells. Recent studies in snail, fly and rat suggest that caspase-3 also functions as a regulatory molecule in neurogenesis and synaptic activity. In this study, in addition to providing an overview of the mechanism of caspase-3 activation, we review genetic and pharmacological studies of apoptotic and nonapoptotic functions of caspase-3 and discuss the regulatory mechanism of caspase-3 for executing nonapoptotic functions in the central nervous system. Knowledge of biochemical pathway(s) for nonapoptotic activation and modulation of caspase-3 has potential implications for the understanding of synaptic failure in the pathophysiology of neurological disorders. Fine-tuning of caspase-3 lays down a new challenge in identifying pharmacological avenues for treatment of many neurological disorders.

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Caspase activity is essential for long‐term potentiation

Cited by 60 publications

References 121 publications

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth

Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor

Neuronal caspase-3 signaling: not only cell death

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