title: 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.
authors.affiliation: Department of Neuroscience, Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Biology, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Megill
authors.affiliation: Department of Pathology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Department of Neuroscience, Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Kirkwood
authors.affiliation: Department of Neuroscience, Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland, United States of America; Department of Biology, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Hey-Kyoung
authors.initials: HK
authors.lastname: Lee
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency* / Q000378:metabolism; D056654:CA3 Region, Hippocampal / Q000473:pathology* / Q000503:physiopathology*; D005071:Evoked Potentials; D019706:Excitatory Postsynaptic Potentials; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000473:pathology / Q000503:physiopathology; D017966:Pyramidal Cells / Q000473:pathology; D013569:Synapses / Q000473:pathology*
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse