Circuit Analysis of Synaptic Dysfunctions in the CA3 Area of BACE1 Knockout Mice
Circuit Analysis of Synaptic Dysfunctions in the CA3 Area of BACE1 Knockout Mice
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Date
2012
Authors
Wang, Hui
Advisor
Quinlan, Elizabeth
Lee, Hey-Kyoung
Lee, Hey-Kyoung
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Abstract
Beta-amyloid precursor protein cleavaging enzyme 1 (BACE1), a major neuronal beta-secretase critical for the formation of beta-amyloid (Abeta) peptide, is thought to be one of the key therapeutic targets that can prevent the progression of Alzheimer's disease (AD). Although complete ablation of BACE1 gene prevents Abeta formation, I found that at the mossy fiber projections in CA3 area of hippocampus, where BACE1 is highly expressed in normal brain, BACE1 knockout (KO) mice display reduced presynaptic function, as measured by an increase in paired-pulse facilitation ratio, and abolished mossy fiber LTP, which is very likely due to presynaptic Ca2+ signaling abnormality.
In order to determine the function of BACE1 in an intact CA3 circuit, whole-cell recordings were performed from pyramidal cells and inhibitory interneurons in the CA3 area that receive mossy fiber inputs. My analyses revealed a decrease in presynaptic release at mossy fiber synapses onto CA3 pyramidal cells of BACE1 KO mice as determined by a significantly reduction in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and enhanced paired-pulse facilitation ratio. In contrast, BACE1 KO mice do not exhibit significant dysfunction at mossy fiber input on CA3 inhibitory interneurons. However, presynaptic function at inhibitory input on CA3 pyramidal neurons is impaired in BACE1 KOs, as seen from a reduction in paired-pulse depression of inhibitory postsynaptic responses and a significant decrease in the frequency of miniature inhibitory postsynaptic currents (mIPSCs).
Finally, to restore the deficits caused by BACE1 inhibition, I demonstrated that brief application of nicotine can improve presynaptic release and recover mossy fiber LTP in BACE1 KOs by activating alpha7-nAChRs, which recruits Ca2+ induced Ca2+ release to rescue the abnormal presynaptic Ca2+ signaling.
In summary, my studies suggest that BACE1 may play a critical role in regulating presynaptic function, especially activity-dependent strengthening of presynaptic release. The presynaptic dysfunction seen in BACE1 KOs is likely specified by the postsynaptic target, the CA3 pyramidal neurons, independent of the type of inputs. And nicotine or alpha7-nAChR agonists may be a potential pharmacological means to circumvent the synaptic dysfunctions caused by BACE1 inhibition.