By using gene knockdown and knockout mice, we demonstrated that the BAD-BAX-caspase-3 cascade is to induce NMDA receptor-dependent LTD and AMPA receptor endocytosis, but not for mGluR-LTD or long-term potentiation of synaptic transmission (Li et al., Cell 2010;Jiao et al., Neuron 2011). Unlike in apoptosis, however, BAD is activated only transiently and mildly leading to modest and transient caspase-3 activation insufficient to induce cell death. Our findings reveal a core signaling cascade for LTD induction and provide evidence that mechanistic and quantitative differences in caspase-3 activation are critical for determining whether it induces LTD or apoptosis. To determine if the BAD-BAX-caspase-3 cascade regulates other properties of synaptic transmission, we measured evoked and spontaneous excitatory synaptic response, and using electron microscopy to assess the ultrastructure of synapse in the knockout mice. To identify downstream effectors of the BAD-BAX-caspase-3 cascade that promotes LTD and AMPA receptor endocytosis, we collaborate with Dr. Sandy Markey to search for caspase substrates that are cleaved in LTD. We will use electrophysiology to determine if the identified caspase substrate is involved in LTD induction. We have previously collaborated with Dr. Richard Youle to examine the function of BAX in the maintenance of mitochondrial morphology (Norris et al., Cell Death and Differentiation 2010). Mitochondria morphology is important for mitochondria to support the development and function of synapses. To test whether the BAD-BAX-caspase-3 cascade regulates mitochondria morphology, we have examined mitochondria in BAD, BAX and caspase-3 knockout mice. We identified a fragmented mitochondrial phenotype and mitochondrial fusion defect in BAD and BAX knockout neurons. Therefore, we propose that BAD is an important activator of BAX for maintenance of mitochondria morphology in neurons.
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