Aβ_1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer’s disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ_1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ_1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (I_NaP) blocker, dose-dependently reduced Aβ_1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ_1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

The transgenic animals have been yielding invaluable insights into amyloid pathology by replicating the key features of Alzheimer’s disease (AD). However, there is no clear relationship between senile plaques and memory deficits. Instead, cognitive impairment and synaptic dysfunction are particularly linked to a rise in Aβ_1-42 oligomer level. Thus, injection of Aβ_1-42 oligomers into a specific brain region is considered an alternative approach to investigate the effects of increased soluble Aβ species without any plaques, offering higher controllability, credibility and validity compared to the transgenic model. The hippocampal CA1 (cornu ammonis 1) region is selectively affected in the early stage of AD and specific targeting of CA1 region directly links Aβ oligomer-related pathology with memory impairment in early AD. Next, the inhibitory avoidance (IA) task, a learning paradigm to assess the synaptic basis of CA1-dependent contextual learning, triggers training-dependent synaptic plasticity similar to in vitro HFS (high-frequency stimulation). Given its reliability in assessing contextual memory and synaptic plasticity, this task provides an effective framework for studying early stage AD-related memory deficit. Therefore, in this review, we will focus on why Aβ_1-42 oligomer injection is a valid in vivo model to investigate the early stage of AD and why dorsal CA1 region serves as a target area to understand the adverse effects of Aβ_1-42 oligomers on contextual learning through the IA task.

Aβ1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer's disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability which may also contribute to cognitive deficits is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (INaP) blocker, dose-dependently reduced Aβ1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

The transgenic models have been yielding invaluable insights into amyloid pathology as they mimic the nature of Alzheimer’s disease (AD). However, there is no clear relationship between senile plaques and memory deficits. Instead, cognitive impairment and synaptic dysfunction are particularly linked to a rise in Aβ1-42 oligomer level. Thus, injection of Aβ1-42 oligomers into a specific brain region is considered as an alternative to investigate the effects of increased soluble Aβ species without any plaques owing to its controllability, credibility and validity. Despite the homogeneous cytoarchitecture, the hippocampal CA1 (Cornu ammonis 1) region displays topographical heterogeneity and is differentially affected in the early stage of AD. Moreover, specific targeting of CA1 subregion is important not to miss axis-linked implications in the behavioral consequences. Next, inhibitory avoidance (IA) task is a relevant learning paradigm to assess synaptic basis of hippocampal CA1-dependent contextual memory formation. This one-trial task is based on associating the training context with the aversive stimulus after the foot shock and triggers training-dependent synaptic plasticity similar to in vitro HFS (High-frequency stimulation). Therefore, in this review, we will focus on why injection of Aβ1-42 oligomers is a valid in vivo model to investigate the early stage of AD and why dorsal CA1 region is a target area to understand the adverse effects of Aβ1-42 oligomers on contextual learning in the IA task.