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Lack of β-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo

  • Matej VnencakEmail author
  • Marieke L. Schölvinck
  • Stephan W. Schwarzacher
  • Thomas Deller
  • Michael Willem
  • Peter JedlickaEmail author
Original Article

Abstract

BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer’s disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and excitability in the entorhinal–dentate circuitry.

Keywords

Electrophysiology Local field potentials (LFPs) Population spike LTP Alzheimer’s disease 

Notes

Funding

This study was funded by the Deutsche Forschungsgemeinschaft (DFG) (JE 528/6-1) and by the Alzheimer Forschung Initiative e.V. (15038).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of Clinical Neuroanatomy, Neuroscience CenterGoethe UniversityFrankfurt am MainGermany
  2. 2.Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck SocietyFrankfurt am MainGermany
  3. 3.BioMedical Center, BiochemistryLudwig-Maximilians-UniversityMunichGermany
  4. 4.ICAR3R-Interdisciplinary Centre for 3Rs in Animal Research, Faculty of MedicineJustus-Liebig-UniversityGiessenGermany
  5. 5.Otorhinolaryngology, Head and Neck Surgery, Turku University HospitalUniversity of TurkuTurkuFinland

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