Cysteine proteases of the caspase family play central roles in excecuting the cell death process in neurons during development of the nervous system and in neurodegenerative disorders. Recent findings suggest that caspases may also play roles in modulating neuronal plasticity in the absence of cell death. We previously reported that caspases can be activated in dendrites and synapses in response to activation of glutamate receptors. In the present study we demonstrate that the GluR1 subunit of the AMPA subtype of glutamate receptor is directly cleaved by caspase-3, and provide evidence that the cleavage of this subunit modulates neuronal excitability in ways that suggest important roles for caspases in regulating synaptic plasticity and cell survival. Whole-cell patch-clamp recordings in cultured rat hippocampal neurons showed that caspase activation in response to apoptotic stimuli selectively decreases AMPA channel activity without decreasing NMDA channel activity. Perfusion of neurons with recombinant caspase-3 resulted in a decreased AMPA current, demonstrating that caspase-3 activity is sufficient to suppress neuronal responses to glutamate. Exposure of radiolabeled GluR1 to recombinant caspase-3 resulted in cleavage of GluR1, demonstrating that this glutamate receptor protein is a direct substrate of this caspase. Our findings suggest roles for caspases in the modulation of neuronal excitability in physiological settings, and also identify a mechanism whereby caspases ensure that neurons die by apoptosis rather than excitotoxic necrosis in developmental and pathological settings.
"The study of Gilman and Mattson  on neurons in apoptotic state have shown that activation of caspase-3 is followed by degradation of AMPA receptor, a part of R1 and R4 subunits of glutamate receptors, but not the NMDA receptors. Furthermore, it was shown that cultured hippocampal neurons treated with caspase-3 inhibitor exhibited increased function of AMPA receptors, what suggests that a low level of caspase activity is essential for reducing glutamate sensitivity in physiological conditions . A study of Li et al.  merging overexpression of endogenous inhibitors and pharmacological inhibition of caspase-3 has shown that mitochondria mediated activation of caspase-3 is required for LTD in cell culture of CA1 hippocampal neurons. "
"fficking by cleaving the AMPAR subunits GluR1 ( GluA1 ) ( Lu et al . 2002 ) and GluR4 ( GluA4 ) ( Chan et al . 1999 ; Glazner et al . 2000 ) , the AMPAR - associated proteins post - synaptic density - 95 ( PSD - 95 ) ( Liu et al . 2010 ) , CaMKII , calcineurin A , and the activity - regulated cytoskeleton - associated protein ( Arc ) ( Fig . 2 ) ( Lu et al . 2002 ; D ' Amelio et al . 2011 ; Jo et al . 2011 ; Snigdha et al . 2012 ) . LTD induction also requires caspase - 3 - mediated proteolysis of RAC - alpha serine / threonine - protein kinase ( Akt1 ) ( Li et al . 2010 ) . Active Akt1 suppresses LTD by phosphorylating and inhibiting the glycogen synthase kinase - 3β ( GSK3β ) , which also"
[Show abstract][Hide abstract] ABSTRACT: The classical view of mitochondria as housekeeping organelles acting in the background to simply maintain cellular energy demands has been shaken by mounting evidence of their direct and active participation in synaptic plasticity in neurons. Time-lapse imaging has revealed that mitochondria are motile in dendrites, with their localization and fusion and fission events regulated by synaptic activity. The positioning of mitochondria directly influences function of nearby synapses through multiple pathways including control over local concentrations of ATP, Ca+2, and reactive oxygen species. Recent studies have also shown that mitochondrial protein cascades classically associated with apoptosis are involved in neural plasticity in healthy cells. These findings link mitochondria to the plasticity- and metaplasticity-associated activity-dependent transcription factor MEF2 further repositioning mitochondria as potential command centers for regulation of synaptic plasticity. Intriguingly, MEF2 and mitochondrial functions appear to be intricately intertwined, as MEF2 is a target of mitochondrial apoptotic caspases and in turn, MEF2 regulates mitochondrial genome transcription essential for production of superoxidase and hydrogen peroxidase. Here, we review evidence supporting mitochondria as central organelles controlling the spatiotemporal expression of neuronal plasticity, and attempt to disentangle the MEF2-mitochondria relationship mediating these functions.This article is protected by copyright. All rights reserved
The Journal of Physiology 12/2014; 593(16). DOI:10.1113/jphysiol.2014.282459 · 5.04 Impact Factor
"This concept implies a vicious circle because the lack of neurotrophic factors modifies energy metabolism in neurons and because neurotrophic factors act locally on synaptic terminals to improve mitochondrial function (Guo and Mattson, 2000) and synaptic function through regulation of the activation of signaling pathways (Chapleau and Pozzo-Miller, 2012). A lack of neurotrophic factors triggers apoptotic cascades in synaptic terminals (Ambacher et al., 2012), which results in the degeneration of axons and dendrites (Lu et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: Experimental evidence has revealed the role of mitochondria in various aspects of neuronal physiology. Mitochondrial failure results in alterations that underlie the pathogeneses of many neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease (HD) and amyotrophic lateral sclerosis. The mitochondrial toxin 3-nitropropionic acid (3-NP) has been used to model failure; for example, systemic administration of 3-NP imitates the striatal degeneration that is exhibited in the postmortem tissue of patients afflicted with HD. We have demonstrated that low, sub-chronic doses of 3-NP are sufficient to initiate the damage to striatal neurons that is associated with changes in neurotrophin expression levels. However, the mechanisms underlying the alterations in neuronal activity and neurotransmission due to 3-NP-induced mitochondrial dysfunction remain to be elucidated. In this paper, we focus on how corticostriatal transmission and its modulation by neurotrophins are altered in vivo after 5 days of mitochondrial inhibition with 3-NP.
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