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 language | English (US) |
---|---|
Pages (from-to) | 1215-1221 |
Number of pages | 7 |
Journal | Journal of Neurochemistry |
Volume | 115 |
Issue number | 5 |
DOIs | |
State | Published - 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