Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization.
NMDA receptor-dependent synaptic modifications, such as long-term potentiation (LTP) and long-term depression (LTD), are essential for brain development and function. LTD occurs mainly by the removal of AMPA receptors from the postsynaptic membrane, but the underlying molecular mechanisms remain unclear. Here, we show that activation of caspase-3 via mitochondria is required for LTD and AMPA receptor internalization in hippocampal neurons. LTD and AMPA receptor internalization are blocked by peptide inhibitors of caspase-3 and -9. In hippocampal slices from caspase-3 knockout mice, LTD is abolished whereas LTP remains normal. LTD is also prevented by overexpression of the anti-apoptotic proteins XIAP or Bcl-xL, and by a mutant Akt1 protein that is resistant to caspase-3 proteolysis. NMDA receptor stimulation that induces LTD transiently activates caspase-3 in dendrites, without causing cell death. These data indicate an unexpected causal link between the molecular mechanisms of apoptosis and LTD.
Li
Zheng
Z
The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. lizheng2@mail.nih.gov
Jo
Jihoon
J
Jia
Jie-Min
JM
Lo
Shih-Ching
SC
Whitcomb
Daniel J
DJ
Jiao
Song
S
Cho
Kwangwook
K
Sheng
Morgan
M
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3