Impaired Learning and Memory Ability Induced by a Bilaterally Hippocampal Injection of Streptozotocin in Mice: Involved With the Adaptive Changes of Synaptic Plasticity.

Cong-Cong Qi,Jin-Fang Ge,Jing-Xian Xu,Xing-Xing Chen,Xin-Ran Gao,Sen Liu

doi:10.3389/fnagi.2021.633495

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency.Objective: To establish an AD-like mice model, investigate the behavioral performance, and explore the potential mechanism.Methods: Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL/6 mice, and the behavioral performance was observed. The serum concentrations of insulin and nesfatin-1 were measured by ELISA, and the activation of hippocampal microglia and astrocytes was assessed by immunohistochemistry. The protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the pre-frontal cortex (PFC) was detected via western blotting.Results: The STZ-microinjected model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice, together with an increase abundance of Aβ1−42 and Tau in the hippocampus and PFC. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-β-catenin/β-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3β (ser9)/GSK-3β were reduced in the hippocampus.Conclusion: A bilateral hippocampal microinjection of STZ could induce not only AD-like behavioral performance in mice, but also adaptive changes of synaptic plasticity against neuroinflammatory and endocrinal injuries. The underlying mechanisms might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.

Highlights

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by a progressive deterioration of cognitive functions (Zameer et al, 2019)
The complex is responsible for the membrane binding between synaptic terminals and the neurotransmitter receptors including N-methyl-Daspartate receptor (NMDARs) and AMPAR in the postsynaptic density (Chen et al, 2015). These results suggest that NMDARs perhaps take part in the etiopathology of neuropsychiatric injury in AD, with different physiological and molecular characteristics for different subunits of NMDARs
In the open field test (OFT), there was no significant difference between groups with regards to the latency (t (24) = −1.439, P = 0.173; Figure 3C) and frequency (t (24) = −1.950, P = 0.063; Figure 3D) to the center, and duration in the center (t (24) = 0.856, P = 0.401; Figure 3E), the bilaterally hippocampal STZ-injected mice showed significantly decreased total ambulatory distance traveling in the area (t (24) = 2.474, P = 0.024; Figure 3F), as well as the ambulatory distance (t (24) =2.611, P = 0.017; Figure 3G) and ambulatory time (t (24) = 2.598, P = 0.017; Figure 3H) in the center zone as compared with the control ones

Summary

Introduction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by a progressive deterioration of cognitive functions (Zameer et al, 2019). Targeted at increasing the activity of cholinergic neurons, cholinesterase inhibitors such as tacrine are clinically used in the treatment for AD with limited effect, but they could not slow or reverse the progress of AD. Sodium oligomannate has received its first approval in 2019 in China for the treatment of mild to moderate AD (Wang et al, 2019; Syed, 2020), it is still one of the most imperative scientific issues to explore the pathogenesis of AD clearly, find potential therapeutic targets, and develop effective therapeutic agents in the field of neuropsychiatric diseases and public health. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency

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Conclusion