Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction

Dawei Zhang, Chen Zhang, Angela Ho, Alfredo Kirkwood, Thomas C. SüDhof, Jie Shen

Research output: Contribution to journalArticle

Abstract

Synaptic dysfunction is widely thought to be a pathogenic precursor to neurodegeneration in Alzheimer's disease (AD), and the extent of synaptic loss provides the best correlate for the severity of dementia in AD patients. Presenilins 1 and 2 are the major causative genes of early-onset familial AD. Conditional inactivation of presenilins in the adult cerebral cortex results in synaptic dysfunction and memory impairment, followed by age-dependent neurodegeneration. To characterize further the consequence of presenilin inactivation in the synapse, we evaluated the temporal development of pre-synaptic and post-synaptic deficits in the Schaeffer-collateral pathway of presenilin conditional double knockout (PS cDKO) mice prior to onset of neurodegeneration. Following presenilin inactivation at 4-weeks, synaptic facilitation and probability of neurotransmitter release are impaired in PS cDKO mice at 5-weeks of age, whereas post-synaptic NMDA receptor (NMDAR)-mediated responses are normal at 5-weeks but impaired at 6-weeks of age. Long-term potentiation induced by theta burst stimulation is also reduced in PS cDKO mice at 6-weeks of age. These results show that loss of presenilins results in pre-synaptic deficits in short-term plasticity and probability of neurotransmitter release prior to post-synaptic NMDAR dysfunction, raising the possibility that presenilins may regulate post-synaptic NMDAR function in part via a trans-synaptic mechanism.

Original languageEnglish (US)
Pages (from-to)1215-1221
Number of pages7
JournalJournal of Neurochemistry
Volume115
Issue number5
DOIs
StatePublished - Dec 2010

Keywords

  • Alzheimer's disease
  • Conditional knockout
  • LTP
  • NMDA receptor
  • Neurodegeneration
  • Neurotransmitter release
  • Synaptic dysfunction
  • Synaptic facilitation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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