Postsynaptic target specific synaptic dysfunctions in the CA3 area of BACE1 knockout mice

Research output: Contribution to journalArticle

Abstract

Beta-Amyloid precursor protein cleaving enzyme 1 (BACE1), a major neuronal b-secretase critical for the formation of bamyloid (Ab) 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 Ab 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. Copyright:

Original languageEnglish (US)
Article numbere92279
JournalPLoS One
Volume9
Issue number3
DOIs
StatePublished - Mar 17 2014

Fingerprint

Amyloid beta-Protein Precursor
amyloid
Knockout Mice
mice
Enzymes
enzymes
interneurons
Interneurons
proteins
Inhibitory Postsynaptic Potentials
Fibers
synapse
Synapses
Hippocampal CA3 Region
Amyloid Precursor Protein Secretases
synaptic transmission
Pyramidal Cells
Excitatory Postsynaptic Potentials
Patch-Clamp Techniques
Alzheimer disease

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Postsynaptic target specific synaptic dysfunctions in the CA3 area of BACE1 knockout mice. / Wang, Hui; Megill, Andrea; Wong, Philip Chun; Kirkwood, Alfredo; Lee, Hey-Kyoung.

In: PLoS One, Vol. 9, No. 3, e92279, 17.03.2014.

Research output: Contribution to journalArticle

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