Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Abstract

Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (A β). However, Aβ -independent effects of mutant PS1 on neuronal Ca 2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca 2+ chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3×TgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.

Neuronal Calcium Homeostasis and Dysregulation

“…These results suggest that increased ER Ca 2þ release in PS1 knock-in mice results in (a compensatory) inactivation=desensitization of NMDA receptors. Similar results were found in neurons of so-called triple transgenic mice (that in addition to the PS1 mutant knock-in express APP and tau protein mutations) (92). Interestingly, Ab also has been found to inhibit glutamatergic synaptic transmission (through NMDA receptor stimulation and possibly desensitization).…”

“…For example, it was found that in mutant PS1 knock-in mice LTP was not impaired, but the effect of cholinergic transmission was reversed (i.e., instead of enhancing LTP, cholinesterase inhibitors caused LTP reduction in these mice). It was found that NMDA receptor currents in these mice were reduced but could be restored to normal levels by intraneuronal Ca 2þ chelation (92). These results suggest that increased ER Ca 2þ release in PS1 knock-in mice results in (a compensatory) inactivation=desensitization of NMDA receptors.…”

Age-Dependent Impairment of Spine Morphology and Synaptic Plasticity in Hippocampal CA1 Neurons of a Presenilin 1 Transgenic Mouse Model of Alzheimer's Disease

“…Facilitated LTP in mutPS1 mice at 4 -5 months of age seems to be a consistent finding in mice overexpressing mutant PS1, but also in PS1 M146V knock-in mice without overexpression (Wang et al, 2009) suggesting that the mutation itself facilitates LTP. Recently, Puzzo et al (2008) strongly supported a model for A␤ effects in which low concentrations play a novel positive, modulatory role on LTP, whereas high concentrations play the wellknown detrimental effect (Jacobsen et al, 2006;Lacor et al, 2007;Shankar et al, 2007;Venkitaramani et al, 2007).…”

“…Priller et al (2007) showed that cultured hippocampal neurons expressing a mutant PS1 exhibited an inhibition of evoked excitatory synaptic currents while the same mutation induces an increased LTP (Dewachter et al, 2008). Likewise, Wang et al (2009) reported that PS1 mutant knock-in mice showed an increased LTP which coincides with decreased NMDA currents at the same age.…”

EEG and Granular Osmiophilic Elements in Early-Onset Alzheimer’s Disease

“…The cholinergic loss is an early marker of memory deficits in Alzheimer's disease, and PS1 mutant knock-in mice show impairment of cholinergic modulation in hippocampal plasticity, providing evidence of cholinesterase inhibitor therapy in dementia. However, the ability of these drugs to lower the epileptic threshold should suggest caution in their use in EOAD [7] .…”