Postsynaptic Target Specific Synaptic Dysfunctions in the CA3 Area of BACE1 Knockout Mice

Abstract

Beta-amyloid precursor protein cleaving enzyme 1 (BACE1), a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, is considered one of the key therapeutic targets that can prevent the progression of Alzheimer’s disease (AD). Although a complete ablation of BACE1 gene prevents Aβ formation, we previously reported that BACE1 knockouts (KOs) display presynaptic deficits, especially at the mossy fiber (MF) to CA3 synapses. Whether the defect is specific to certain inputs or postsynaptic targets in CA3 is unknown. To determine this, we performed whole-cell recording from pyramidal cells (PYR) and the stratum lucidum (SL) interneurons in the CA3, both of which receive excitatory MF terminals with high levels of BACE1 expression. BACE1 KOs displayed an enhancement of paired-pulse facilitation at the MF inputs to CA3 PYRs without changes at the MF inputs to SL interneurons, which suggests postsynaptic target specific regulation. The synaptic dysfunction in CA3 PYRs was not restricted to excitatory synapses, as seen by an increase in the paired-pulse ratio of evoked inhibitory postsynaptic currents from SL to CA3 PYRs. In addition to the changes in evoked synaptic transmission, BACE1 KOs displayed a reduction in the frequency of miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in CA3 PYRs without alteration in mEPSCs recorded from SL interneurons. This suggests that the impairment may be more global across diverse inputs to CA3 PYRs. Our results indicate that the synaptic dysfunctions seen in BACE1 KOs are specific to the postsynaptic target, the CA3 PYRs, independent of the input type.

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

“…Although associated with β‐cleavage of APP, leading to greater Aβ and βCTF expression, attenuation of Bace1 levels by MCS may indicate a counterintuitive normalization of APP processing in vulnerable neurons that reflects the importance of steady‐state Aβ and βCTF levels, underscoring the importance of evaluating βCTF expression in DS/AD models (Jiang et al, ). Alternatively, Bace1 deficiency may be considered detrimental, as a loss of Bace1 expression impairs myelination (Hu, Hu, Dai, Trapp, & Yan, ) and causes hippocampal synaptic deficits (Petrus & Lee, ; Wang et al, ; Zhu et al, ), illustrating the need for normative Bace1 levels. MCS also restores the normal expression of two truncated forms of tau ( Mapt2N6D and Mapt2N6P ).…”

“…Importantly, normalizing Dyrk1a gene dosage in tri- ing the importance of evaluating bCTF expression in DS/AD models (Jiang et al, , 2016. Alternatively, Bace1 deficiency may be considered detrimental, as a loss of Bace1 expression impairs myelination (Hu, Hu, Dai, Trapp, & Yan, 2015) and causes hippocampal synaptic deficits (Petrus & Lee, 2014;Wang et al, 2014;Zhu et al, 2016), illustrating the need for normative Bace1 levels. MCS also restores the normal expression of two truncated forms of tau (Mapt2N6D and Mapt2N6P).…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…[38][39][40] As a putative correlate of their learning and memory deficits, Wang et al found that activitydependent potentiation at the mossy-fiber -CA3 synapse in the hippocampus of BACE1-deficient mice is substantially impaired. 41,42 Given that AD patients, in which BACE1 activity should be elevated, often display lowered seizure threshold (see above), it appeared counterintuitive at first that BACE1 knockout mice develop epileptic seizures, too, as reported by 2 groups. 43,44 BACE1 -electrophysiological effects beyond Alzheimer's disease Evidence accumulates that BACE1 does not exclusively affect the brain by cleavage of APP.…”

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

“…This would be consistent with the reduced inhibitory postsynaptic currents upon BACE1 inhibition in hippocampal neurons from dissociated cultures as well as organotypic hippocampal slices, as observed here and previously in acute hippocampal slices from BACE1 KOs. 67 On the other hand, though, the levels of the substrate candidate NLGN2 would be expected to be increased as well and may sequester the increased MDGA1 levels, thus not resulting in a change in inhibitory synapse formation. Yet, other BACE1 substrates, such as SEZ6, voltage-gated sodium channels, Jagged, and Nrg1, also affect directly or indirectly synaptic transmission.…”

“…Among other phenotypes, BACE1 KO mice present with reduced inhibitory transmission in the hippocampus, but excitatory transmission is affected as well. 29,67 While it is not yet exactly clear which BACE1 substrates contribute to these phenotypes, it is interesting that several BACE1 substrates and substrate candidates have a function in synaptic transmission. This includes SEZ6, 27,28 Neuroligin-2 (NLGN2), 68 and our newly identified BACE1 substrate MDGA1.…”