Abstract
The N-methyl-D-aspartate receptor is a critical molecule for synaptic plasticity and cognitive function. Impaired synaptic plasticity is thought to contribute to the cognitive impairment associated with Alzheimer’s disease (AD). However, the neuropathophysiological alterations of N-methyl-D-aspartate receptor (NMDAR) function and synaptic plasticity in hippocampal CA1 in transgenic rodent models of AD are still unclear. In the present study, APP/PS1 mice were utilized as a transgenic model of AD, which exhibited progressive cognitive impairment including defective working memory, recognition memory, and spatial memory starting at 6 months of age and more severe by 8 months of age. We found an impaired long-term potentiation (LTP) and reduced NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs) in the hippocampal CA1 of APP/PS1 mice with 8 months of age. Golgi staining revealed that dendrites of pyramidal neurons had shorter length, fewer intersections, and lower spine density in APP/PS1 mice compared to control mice. Further, the reduced expression levels of NMDAR subunits, PSD95 and SNAP25 were observed in the hippocampus of APP/PS1 mice. These results suggest that NMDAR dysfunction, impaired synaptic plasticity, and disrupted neuronal morphology constitute an important part of the neuropathophysiological alterations associated with cognitive impairment in APP/PS1 mice.
Highlights
Alzheimer’s disease is a progressive neurologic disorder characterized by cognitive dysfunction, mainly learning and memory
To understand the structural and molecular basis of altered synaptic plasticity, the neuronal morphology and expression levels of synapse-associated proteins, including glutamate receptor subunits, postsynaptic density 95 (PSD95), and synaptosomal-associated protein 25 (SNAP25), were determined using Golgi staining and western blotting, respectively. These results suggested that N-methyl-D-aspartate receptor (NMDAR) dysfunction, impaired synaptic plasticity, and disrupted neuronal morphology constitute an important part of the neuropathophysiological alterations associated with cognitive impairment in APP/PS1 mice
The results showed that NMDAR spontaneous excitatory postsynaptic currents (sEPSCs) were largely diminished in 8-month-old APP/PS1 mice [Figure 4G; unpaired t-test: t(20) = 3.885; P = 0.0009]
Summary
Alzheimer’s disease is a progressive neurologic disorder characterized by cognitive dysfunction, mainly learning and memory. The hippocampal CA1 area is one of the most influenced regions in AD (Gómez-Isla et al, 1997; Llorens-Martín et al, 2014; Yang et al, 2018), which is involved in spatial orientation, learning, and different aspects of memory, such as consolidation and retrieval (Bartsch et al, 2011; Fouquet et al, 2012). The impairment of these functions is related to the core clinical symptom in AD patients (LlorensMartín et al, 2014). In animal models of AD, studies have found that abnormalities of neuronal morphology and expression levels of synapse-associated proteins contribute to the impaired neural plasticity in the hippocampal CA1 in AD models (Le Douce et al, 2020; Wang et al, 2020; Li et al, 2021)
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