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.
Highlights
C-secretase-dependent manner (Yu et al 2001; Feng et al 2004; Saura et al 2004; Tabuchi et al 2009; WinesSamuelson et al 2010)
By 5 week of age, we found that synaptic facilitation of excitatory post-synaptic current (EPSC) amplitude was significantly reduced at stimulation frequencies higher than 5 Hz in PS presenilin conditional double knockout mice (cDKO) mice, whereas synaptic facilitation elicited at 1 Hz stimulus was not changed (Fig. 1b–d)
Loss of presenilin function and accumulation of b-amyloid peptides can induce synaptic impairment in the absence of neuronal degeneration (Hsia et al 1999; Saura et al 2004; Zhang et al 2009), suggesting that synaptic dysfunction may be a pathogenic precursor before frank neurodegeneration in Alzheimer’s disease (AD)
Summary
C-secretase-dependent manner (Yu et al 2001; Feng et al 2004; Saura et al 2004; Tabuchi et al 2009; WinesSamuelson et al 2010). Inactivation of presenilin in conditional double knockout (PS cDKO) results in striking pre- and post-synaptic impairments prior to progressive neurodegeneration that resemble key neuropathological features of AD, raising the possibility that partial loss of presenilin function may contribute to synaptic dysfunction and neurodegeneration in AD (Saura et al 2004; Shen and Kelleher 2007; Zhang et al 2009; Wines-Samuelson et al 2010). We performed a detailed electrophysiological analysis in the hippocampal Schaeffer-collateral pathway to establish temporal development of the pre- and post-synaptic defects caused by loss of presenilin in PS cDKO mice. Our study suggests that pre-synaptic deficit in neurotransmitter release is the initial impairment prior to post-synaptic NMDAR-mediated dysfunction in PS cDKO mice
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