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Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission

Song Jiao1, Zheng Li

  • 1Unit on Synapse Development and Plasticity, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.

Neuron
|May 26, 2011
PubMed

Insights

Caspase-3 activation by the BAD-BAX cascade is crucial for NMDA receptor-dependent long-term depression (LTD) but not cell death. Fine-tuning caspase-3 activity distinguishes between these neuronal pathways.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Death Pathways

Background:

  • Caspases are known for apoptosis but also play roles in nonapoptotic processes.
  • NMDA receptor-dependent long-term depression (LTD) involves synaptic transmission modulation.
  • Mechanisms of caspase activation and neuronal survival during LTD are not fully understood.

Purpose of the Study:

  • To elucidate the role of the BAD-BAX cascade in caspase-3 activation during NMDA receptor-dependent LTD.
  • To investigate how neurons survive LTD despite caspase activation.
  • To differentiate the signaling pathways leading to LTD versus apoptosis.

Main Methods:

  • Investigated the BAD-BAX cascade in the context of NMDA receptor-dependent LTD.
  • Assessed caspase-3 activation, BAD activation, and BAX translocation to mitochondria.
  • Compared caspase activation in NMDA receptor-LTD versus mGluR-LTD.
  • Analyzed the impact of caspase-3 activation intensity and duration on neuronal fate.

Main Results:

  • Caspase-3 is activated by the BAD-BAX cascade specifically for NMDA receptor-dependent LTD.
  • This cascade is sufficient to induce synaptic depression but distinct from apoptotic pathways.
  • BAD activation is moderate and transient, and BAX does not translocate to mitochondria, leading to limited caspase-3 activation.
  • The intensity and duration of caspase-3 activation determine the outcome: LTD or cell death.

Conclusions:

  • The BAD-BAX cascade fine-tunes caspase-3 activation for LTD, preventing cell death.
  • Modulated caspase-3 activity is critical for distinguishing between synaptic plasticity and apoptosis.
  • This study reveals a novel mechanism for regulating caspase activity in nonapoptotic neuronal functions.

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