TY - JOUR
T1 - BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus
AU - Wang, Hui
AU - Song, Lihua
AU - Laird, Fiona
AU - Wong, Philip C.
AU - Lee, Hey Kyoung
PY - 2008/8/27
Y1 - 2008/8/27
N2 - β-Amyloid precursor protein cleavage enzyme 1 (BACE1) has been identified as a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, which is thought responsible for the pathology of Alzheimer's disease (AD). Therefore, BACE1 is one of the key therapeutic targets that can prevent the progression of AD. Previous studies showed that knocking out the BACE1 gene prevents Aβ formation, but results in behavioral deficits and specific synaptic dysfunctions at Schaffer collateral to CA1 synapses. However, BACE1 protein is most highly expressed at the mossy fiber projections in CA3. Here, we report that BACE1 knock-out mice display reduced presynaptic function, as measured by an increase in paired-pulse facilitation ratio. More dramatically, mossy fiber long-term potentiation (LTP), which is normally expressed via an increase in presynaptic release, was eliminated in the knock-outs. Although long-term depression was slightly larger in the BACE1 knock-outs, it could not be reversed. The specific deficit in mossy fiber LTP was upstream of cAMP signaling and could be "rescued" by transiently elevating extracellular Ca2+ concentration. These results suggest that BACE1 may play a critical role in regulating presynaptic function, especially activity-dependent strengthening of presynaptic release, at mossy fiber synapses.
AB - β-Amyloid precursor protein cleavage enzyme 1 (BACE1) has been identified as a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, which is thought responsible for the pathology of Alzheimer's disease (AD). Therefore, BACE1 is one of the key therapeutic targets that can prevent the progression of AD. Previous studies showed that knocking out the BACE1 gene prevents Aβ formation, but results in behavioral deficits and specific synaptic dysfunctions at Schaffer collateral to CA1 synapses. However, BACE1 protein is most highly expressed at the mossy fiber projections in CA3. Here, we report that BACE1 knock-out mice display reduced presynaptic function, as measured by an increase in paired-pulse facilitation ratio. More dramatically, mossy fiber long-term potentiation (LTP), which is normally expressed via an increase in presynaptic release, was eliminated in the knock-outs. Although long-term depression was slightly larger in the BACE1 knock-outs, it could not be reversed. The specific deficit in mossy fiber LTP was upstream of cAMP signaling and could be "rescued" by transiently elevating extracellular Ca2+ concentration. These results suggest that BACE1 may play a critical role in regulating presynaptic function, especially activity-dependent strengthening of presynaptic release, at mossy fiber synapses.
KW - Alzheimer's disease
KW - Beta-secretase
KW - Long-term depression
KW - Long-term potentiation
KW - Paired-pulse facilitation
KW - Presynaptic
UR - http://www.scopus.com/inward/record.url?scp=52049107367&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52049107367&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2440-08.2008
DO - 10.1523/JNEUROSCI.2440-08.2008
M3 - Article
C2 - 18753368
AN - SCOPUS:52049107367
VL - 28
SP - 8677
EP - 8681
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 35
ER -