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Review

Aβ1-42 Oligomer Injection Model: Understanding Neural Dysfunction and Contextual Memory Deficits in Dorsal CA1

by
Min-Kaung-Wint-Mon
1,* and
Dai Mitsushima
1,2
1
Department of Physiology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
2
The Research Institute for Time Studies, Yamaguchi University, Yamaguchi 753-8511, Japan
*
Author to whom correspondence should be addressed.
J. Dement. Alzheimer's Dis. 2025, 2(3), 25; https://doi.org/10.3390/jdad2030025 (registering DOI)
Submission received: 11 March 2025 / Revised: 21 April 2025 / Accepted: 8 July 2025 / Published: 1 August 2025
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Abstract

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 Aβ1-42 oligomer level. Thus, injection of Aβ1-42 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 Aβ1-42 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 Aβ1-42 oligomers on contextual learning through the IA task.

1. Introduction

Alzheimer’s disease (AD) is clinically characterized by an early deficit in episodic memory, concerning spatiotemporal context [1,2], along with extracellular senile plaques and intracellular neurofibrillary tangles (NFT) [3]. The amyloid plaques harbor heterogeneous aggregates of amyloid beta (Aβ) peptides containing 40 (Aβ1-40) or 42 (Aβ1-42) amino acid residues. The amyloid cascade hypothesis initially suggested that Aβ deposition was the primary trigger for AD as it was found to precede and influence the tau pathology [4]. Later, findings revealed that cognitive impairment [5] and synaptic dysfunction [6] were correlated and coincided with a rise in the level of Aβ oligomers [7], even without the formation of amyloid plaques. Consequently, the earliest amyloid toxicities in AD have been modified to be associated with soluble Aβ species [8,9].
The generation of transgenic animals overexpressing proteins related to familial AD, mutant APP (amyloid precursor protein) and PS (presenilin) is based on the amyloid hypothesis that cognitive deficit was linked to plaque formation [10]. With an attempt to replicate the hallmarks of AD including senile plaques, these animals develop age-dependent amyloid pathology in a spatiotemporal manner which closely mimics disease progression in human [4,11]. However, both intrinsic and extrinsic factors modulate the course and outcome of these models [12]. More importantly, merely amyloid plaque (without oligomers) may not account for memory deficits. Moreover, memory impairment cannot also be directly related to a specific dysfunction of a particular brain area [11].
On the other hand, injection of Aβ oligomers into a specific brain region is required as an alternative to understand the effects of increased soluble Aβ species without the presence of any plaques [1]. Unlike the transgenic model, the injection model allows us to control the concentration of Aβ oligomers spatiotemporally and recapitulate the cardinal features of early AD [1]. Using wild-type strain also provides an excellent in vivo model as it can circumvent the potential side effects from the gene mutations. In this context, adverse effects associated with the early Aβ pathology could be identified, thereby preventing cognitive impairment and interfering with advanced neurodegenerative processes [12].
Therefore, we will review why injection of Aβ1-42 oligomers is a valid model to investigate early stage of AD pathology and why dorsal CA1 region is a target area to understand the adverse effects of Aβ1-42 oligomers related to contextual memory.

2. Transgenic Model vs. Injection Model

Transgenic animals, mice and rats [13,14], which express the mutant forms of APP and/or PS gene have enabled us to study AD-related pathologies. These models share a common feature of increased Aβ production, leading to the formation and deposition of amyloid plaques [15]. By recapitulating the neuropathological features of AD [10] and exhibiting a chronic, progressive spectrum of disease [16], these models appear to phenocopy the critical aspects of human AD. Thus, they have represented a promising niche for investigating Aβ pathology and testing the efficacy of therapeutic interventions.
However, these models are based on familial AD-associated gene mutations, which only account for <1% of AD cases [13]. By contrast, clinical AD results from a complex interaction of multiple etiologies, rather than a single involvement of genes [17]. Next, using transgenic animals is time-consuming because it takes months or years to develop Aβ plaques which do not have a clear relationship with cognitive impairments. Resembling advanced AD, they lack early AD-associated pathological changes. The appearance of AD-related phenotypes could be confounded by several factors such as species, age, etc. [12]. More importantly, they develop AD phenotypes not in chronological order and thus are not equivalent to human AD. For example, plaque deposition is preceded by cellular changes and cognitive impairments [10].
To overcome the shortcomings of the transgenic models, injection of Aβ oligomers has been alternatively used. Firstly, the dose of oligomers, the route of injection and the age of animals can be adjusted to minimize the experimental contributing factors. Next, the wild-type strain can circumvent the by-stander effects of the recipient genes derived from the introduction of exogenous genes’ mutations [16]. Moreover, the key advantage of this model can be partly explained by the facts that any brain region can be targeted [1] and the oligomers are rapidly delivered to the area of interest [18]. Most importantly, the greatest benefit of this Aβ-injected model is its credibility as pathological changes are directly triggered by the Aβ oligomers.
As a rise in soluble Aβ species in a certain brain area has been regarded as a starting phenomenon in AD, the oligomer injection is a valid model to investigate the early stage of AD pathology [1,15]. Injecting either natural or synthetic Aβ1-42 oligomers can trigger synaptic dysfunction, astrogliosis and cognitive deficits [18,19,20]. Moreover, these features can be directly linked to specific dysfunction of a particular brain area due to amyloid deposition [18,21]. However, having considered the chronic nature of AD rather than a sudden surge of oligomers, the transgenic models are also recommended to strengthen the findings from the Aβ oligomer-injected models [16].

3. Why Is Understanding Hippocampal CA1 Region Important?

A typical CA1 (cornu ammonis 1) pyramidal neuron (CA1 PN) receives most glutamatergic inputs from the entorhinal cortex (EC). The classical trisynaptic circuitry originates from projections of the EC layer 2 stellate cells, via perforant path (PP), to dentate gyrus (DG) granule cells whose mossy fibers synapse with CA3 PNs, which in turn excite CA1 PNs through the Schaffer collateral (SC) pathway. In addition, direct glutamatergic projections from EC layer 3 PNs also reach CA1 PNs through the temporo-ammonic (TA) pathway. The trisynaptic and monosynaptic circuits convergence at the proximal and distal apical dendrites of CA1 PNs, respectively [22,23]. Finally, CA1 integrates non-spatial information from the lateral entorhinal cortex (LEC) and spatial information from the medial entorhinal cortex (MEC) and provides the primary output of the hippocampus, along with subiculum to the extrahippocampal circuits (Figure 1A) [22].
The hippocampal CA1 region shows functional, intrinsic and synaptic heterogeneities across the longitudinal (dorso-ventral), transverse (proximo-distal) and radial (deep-superficial) axes despite its homogeneous cytoarchitecture [24,25]. Firstly, dorsal CA1 is particularly engaged in the formation of spatial and contextual memories [26], whereas ventral CA1 PNs mediate social-related cues [27]. Along the transverse axis, proximal CA1 PNs exhibit specific firing towards spatial information [28] whereas activation of distal CA1 PNs corresponds to object memory encoding [29,30]. Compared to superficial PNs, deep CA1 PNs are more likely to have place fields and are highly activated during spatial processing (Figure 1B) [31]. This functional diversity reflects differential behavioral role of the hippocampal CA1 subfields in different axes.
These in vivo functional differences can also be contributed by variations in the input–output function of CA1 PNs. Fundamentally, a neuron integrates synaptic inputs and decides whether to fire an action potential (AP) or not. The intrinsic excitability determines its likelihood of firing in response to synaptic inputs and is therefore a crucial link between synaptic input and action potential output (Figure 2A) [32]. Though controlled by independent mechanisms, both forms of plasticity are interdependent [33]. Indeed, both are tightly coupled and bi-directionally adjusted in CA1 PNs so that neuronal activity is maintained to prevent extreme modifications [34].
Yet, how these properties can be directly translated to in vivo responses is controversial owing to the striking topographical differences [35]. For example, ventral CA1 PNs form a weaker and less stable synaptic plasticity [36,37], but are also more excitable than dorsal PNs (Figure 2B) [38]. In the dorsal hippocampus, similar synaptic and intrinsic properties are found at CA1a and CA1c PNs whereas CA1b is distinguished by having lower intrinsic excitability with higher synaptic integrating properties (Figure 2C) [35]. Next, synaptic plasticity of CA1 PNs is more robust in the superficial layer [39] whereas deep CA1 PNs elicit higher firing in the dorsal region (Figure 2D) [35]. These findings suggest that these axis-dependent differences may be related to the expression/function of ion channels as well as receptors underlying intrinsic and synaptic properties.

4. Why Is Hippocampal CA1 Relevant as a Target Area to Study AD Pathology?

The CA1 region, which integrates and processes contextual [40] and spatial information [41], is affected in the early stage of AD. Interestingly, amyloid deposition in the dorsal CA1 follows a spatiotemporal pattern along its anatomical axes [24]. For example, amyloid deposits appear more abundantly in the distal CA1 region than the proximal CA1 across the transverse axis [42]. However, the impact of amyloid on the radial axis of dorsal CA1 is still unknown. Therefore, dorsal CA1 PNs exhibit axis-linked differential susceptibility to amyloid pathology.
Selective vulnerability of CA1 PNs with non-uniform functions may underline selective loss of a particular modality of memory. In the context of functional in vivo consequences, spatial memory deficits can be related to specific dysfunction of dorsal CA1 PNs. Place cells in the dorsal CA1 became damaged along with nearby Aβ aggregates [2], which was accompanied by spatial memory deficits [43]. Yet, there is no clear evidence to characterize such functional impairments in ventral CA1 and across the other two axes.
Owing to the contrasting heterogeneities of CA1, specific targeting of its subfield is important not to miss axis-linked implications in the functional consequences of AD. This leads to direct injection of oligomeric Aβ1-42 into the dorsal CA1 region, which shows Aβ1-42 oligomer-induced deficits in spatial [1] and working memory [44], in association with synaptic dysfunction [45] and Aβ deposition at the injected site [46]. Thus, this CA1 injection model that directly links Aβ oligomers with amyloid-related pathology is valid to advance our understanding of cognitive deficits in AD.

5. Effect of Injecting Aβ1-42 Oligomers into Dorsal CA1 on Contextual Memory

Here, we will focus on contextual memory because of the rapid and stable development of associative learning and its clear relationship with dorsal CA1 [47]. The inhibitory avoidance (IA) task, a learning paradigm for contextual memory, is based on associating the training context with the aversive stimulus after the foot shock [48]. Briefly, contextual learning requires a certain period of exploration prior to shock during which spatial and non-spatial features of the environment are integrated. After receiving shock in the dark region of the box, if the animals have learnt the context–shock pairing, they will stay in the lit area, which they would normally not prefer. Thus, the prolonged latency to enter the dark box indicates formation of contextual memory.
Several studies supported that encoding and retrieval of contextual memory require dorsal CA1 [26]. Similarly to in vitro HFS (high-frequency stimulation), induction of NMDA (N-methyl-D-aspartate)-dependent LTP (long-term potentiation) [47] is followed by the delivery of GluR1-containing AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) to the CA3-CA1 synapses [49], resulting in an increased number of AMPARs [48] after contextual learning. Moreover, the formation of contextual memory strengthens synaptic transmission at both excitatory (AMPAR) and inhibitory (GABAAR) (γ-aminobutyric acid receptor) synapses [48,50] under the cholinergic control [50]. Next, enhanced plasticity in the CA1b region suggests processing and integrating spatial and non-spatial information necessary for establishing contextual memory [51]. That is why this one-trial IA task is a relevant learning paradigm to study the adverse effects of Aβ1-42 oligomers on the dorsal CA1 region.
As CA1b displays robust processing of its mixed input [35] and assembles information necessary for IA learning [51], we aimed to elucidate the effects of Aβ1-42 oligomers on contextual memory by injecting into this target region. Previously, we found that unilateral injection of Aβ1-42 oligomers did not affect learning performance whereas bilateral injection shortened the latency (Figure 3) [52]. This was in accordance with our previous finding that bilateral dorsal CA1 is required for contextual learning [50]. Similarly to our result, Aβ oligomers impaired dorsal CA1-dependent contextual fear memory [53,54] without affecting amygdala-dependent cued fear learning [45]. In addition to contextual learning, other studies showed that bilateral injection of Aβ1-42 oligomers into dorsal CA1 also impaired working [44] and spatial [55,56,57,58] memory as well as object recognition learning performance [58,59].
More importantly, this Aβ1-42 oligomer-induced memory impairment can be directly related to dorsal CA1 dysfunction as E/I (excitatory/inhibitory) imbalance [60], LTP impairment [56] and neuronal hyperexcitability [52] were observed along with concomitant synaptic loss, dendritic degeneration [56] and Aβ1-42 oligomer deposition [52,60] in the target region. Taken together, utilizing the IA task to investigate Aβ1-42 oligomer-induced dorsal CA1-dependent contextual memory impairment will lead to a better understanding of episodic memory impairment in early AD.

6. Aβ1-42 Oligomer-Induced Cellular and Molecular Changes Underlying Contextual Memory Impairment

Neurons modulate their synaptic strength through a process known as LTP, which is considered a cellular correlate of learning and memory. NMDA-dependent LTP is well demonstrated in the CA1 region, which is critical for memory formation [22] and highly vulnerable to Aβ toxicity [24]. Indeed, structural and functional mechanisms play a role in contextual memory formation as it depends on the integrity of hippocampal CA1 region [40] as well as the synaptic [47] and intrinsic properties [61] of CA1 pyramidal neurons. Therefore, any disruption or interference in either neuronal property will adversely impact this CA1-dependent cognitive function.

6.1. Aβ1-42 Oligomer-Induced Changes in Synaptic Plasticity

Synaptic AMPA receptors, mainly composed of GluR1 and GluR2 subunits, are essential for regulating synaptic plasticity [62]. GluR1/2 receptors are incorporated into synapses under synaptic activity, whereas GluA2/3 receptors are continuously delivered to synapses [63]. NMDA receptors (NR1/NR2) can be found at both synaptic and extrasynaptic sites [64]. Synaptic NMDARs, predominantly containing NR2A subunit, require activity-dependent delivery to the synapse [65], while surface expression of extrasynaptic NMDARs, which are made up of mainly NR2B subunit, does not [66]. As synaptic insertion of GluR1 is regarded as a key event in LTP [49], both NMDAR subunits display contrasting roles in synaptic plasticity. For example, expression of GluR1 is promoted by NR2A- and inhibited by NR2B-NMDARs [67]
Early synaptic dysfunction is thought to be triggered by soluble oligomeric Aβ which binds to the neurons and forms clusters at the synapses [68]. Aβ oligomers were found to colocalize with markers of excitatory synapses whereas no colocalization was evident at inhibitory synapses [68]. Moreover, Aβ oligomers have been shown to interfere with the function and trafficking of both AMPARs [69] and NMDARs [70]. These highly signify that synaptotoxic effects of Aβ1-42 oligomers are triggered via excitatory synapses.
Next, Aβ-induced synaptotoxic effects require activation of NMDARs [71] as well as AMPARs [72,73]. Mechanistically, a high level of glutamate at the synapse [66] triggers early aberrant activation of NMDARs and AMPARs [64]. This is plausible as Aβ and VGluT1 were found to presynaptically colocalize on the synaptic boutons [74]. Next, Aβ1-42 oligomers transiently increase presynaptic release of glutamate, together with elevated expression of vGluT1, followed by dramatic depletion of vesicles [75]. Another possible mechanism triggered by Aβ1-42 oligomers is either increased secretion of glutamate from astrocytes [76] and/or impaired reuptake by astrocytes [66,77].
Before a significant synaptic loss, surface expression of both AMPARs and NMDARs [78,79] is downregulated via impaired receptor trafficking or endocytosis [79,80], leading to impaired synaptic transmission and plasticity. Oligomeric Aβ peptide perturbs glutamatergic synaptic transmission via its inhibitory effect on presynaptic release and postsynaptic receptors [81,82]. Next, pharmacological interventions that inhibit the internalization of AMPARs [73,83,84] and NMDARs [80,85] are able to rescue Aβ-induced synaptic deficits. More importantly, many studies have shown that Aβ1-42 oligomers impair LTP [56,86,87,88] both in vitro and in vivo [89] and enhance long-term depression (LTD) [19,90], indicating a net shift in synaptic activity in favor of inhibition.
LTP induction promotes enlargement of spine and growth of new spines [91,92] whereas LTD induction promotes spine shrinkage and retraction [93]. This imbalance would allow Aβ oligomers to exert toxic effects on synapse structure and number. Prior to synaptic degeneration, Aβ destabilizes the mature spines and triggers the morphology of spines towards the immature phenotype [78,94]. These oligomer-induced structural changes [78] are followed by progressive loss of dendritic spines and glutamatergic synapses [79,95]. These adverse effects of Aβ are also mediated via internalization of synaptic AMPARs and NMDARs [79,80,95]. This is consistent with the postulated loss of synaptic plasticity which contributes to synaptic failure and memory dysfunction in AD.
Therefore, Aβ-mediated glutamate surge may initially activate synaptic NMDARs and AMPARs. However, prolonged activation may result in desensitization and internalization of NMDARs and AMPARs. This results in LTP inhibition, synaptic impairment and spine loss, all of which are linked to Aβ-induced memory impairment [66].

6.2. Aβ1-42 Oligomer-Induced Changes in Intrinsic Excitability

Neurons process and encode information by generating trains of APs in terms of frequency and pattern. Indeed, AP is the output of synaptic integration underlined by both passive and active membrane properties of the neuron [96]. Several preclinical and clinical studies have suggested that neuronal hyperexcitability is strongly associated with cognitive impairment in AD [97,98]. Therefore, neuronal hyperexcitability in early AD points to network dysfunction as a critical component of cognitive decline.
Previous studies have demonstrated increased in vivo and in vitro firing activity of CA1 PNs [99,100,101] upon exposure to Aβ1-42 oligomers. It is still controversial how this hyperexcitability can be triggered by Aβ1-42 oligomers. Possible explanations for this phenomenon include altered intrinsic properties [52] and/or E/I imbalance [60,102]. The consequences may not be limited to neuronal hyperexcitability at the single-cell level but could also lead to aberrant activity at the circuit level, both of which have been implicated memory impairment in AD [97,98,103].
Aβ1-42 oligomer-induced E/I imbalance could stem from dysfunctions in glutamatergic or GABAergic system [104]. Oligomeric Aβ could hyperexcite the neurons by disrupting glutamate homeostasis [66,75,76,77], thereby inducing glutamate spillover to extrasynaptic sites and excessive activation of NR2B-containing NMDARs [105]. Moreover, this alteration in E/I dynamics is also attributed to diminished inhibitory function. Aβ1-42 oligomers weaken inhibitory synaptic input by promoting endocytosis of GABAARs [106] and reducing presynaptic GABA release [107]. Moreover, interneurons may undergo changes in their excitability as well as synchronizing function and act together with pyramidal cells to generate aberrant network activity [102].
The intrinsic excitability of neurons is often characterized by their AP frequency and largely influenced by passive and active membrane properties. Firstly, increased membrane resistance and spike numbers after exposure to Aβ1-42 oligomers [52,107,108] indicate the potential effect of Aβ1-42 oligomers on neuronal membrane [109] and morphology [110,111]. This suggests a mechanistic link between altered dendritic morphology and neuronal hyperexcitability triggered by oligomers. Next, dendritic spine loss, known to be associated with cognitive decline, contributes to reduced neuronal surface area, increased membrane resistance and finally neuronal hyperexcitability [110]. These changes result in lowered rheobase and increased firing frequency in response to current injection [111].
The electrical characteristics of neurons are shaped by the activity and density of voltage-gated Na+ (Nav) and K+ (Kv) channels [96]. Studies have showed that Aβ1-42 oligomers increased neuronal excitability via augmentation of Nav 1.6 [100,112,113] and/or suppression of A-type Kv channels [99,114]. In our previous study [52], Aβ1-42 oligomers minimized rheobase to elicit a single AP and triggered hyperexcitability which was dose-dependently blocked by riluzole, highlighting Nav 1.6 as one of the possible targets of Aβ1-42 oligomers.
Taken together, these results suggest that Aβ1-42 oligomers contribute to neuronal hyperexcitability by modifying neuronal intrinsic properties [115]. Increased neural activity is likely a key factor in AD progression as it further elevates Aβ level and exacerbates cognitive deficit [116,117]. However, having considered AD is a complex and multifactorial disease, it is likely that several factors, rather than a single cause, act in conjunction to disrupt cognitive function.

7. Conclusions

Overall, the dorsal CA1 region plays a crucial role in processing contextual and spatial information and exhibits a diverse biophysical and functional topographic heterogeneity. It is particularly vulnerable in the early stages of AD, positioning it as a critical target for understanding the initial pathological changes in AD. Therefore, by delivering Aβ1-42 oligomers directly into the dorsal CA1, amyloid-related pathology and specific memory impairment can be induced without the prolonged time required for development of full-blown pathology in the transgenic AD mice. Next, this approach minimizes potential confounding factors such as neuronal degeneration and cellular biophysical alterations induced by amyloid plaques, thereby allowing a more focused understanding of the disease mechanisms. In addition, the ability to specifically target the dorsal CA1 region and control local distribution of oligomers strengthens its utility as a valuable alternative tool in AD research.
Our research emphasizes the effects of Aβ1-42 oligomers on contextual memory through the inhibitory avoidance (IA) task, a dorsal CA1-dependent learning paradigm. As contextual memory formation depends on synaptic and intrinsic properties of CA1 pyramidal neurons, Aβ1-42 oligomer-induced interference in either process negatively impacts the ability to accomplish this cognitive function. Therefore, this experimental design provides key insights into disruption of episodic memory triggered by Aβ1-42 oligomers. These highlight the detrimental effects of Aβ1-42 oligomers on contextual memory function and support the relevance of the IA task in assessing early stage AD-related memory deficit.
These findings provide a foundation for investigating therapeutic strategies aimed at mitigating AD-related memory deficits. By targeting the dorsal CA1 region, researchers gain critical insights into the initiation and progression of AD pathology and the cellular and molecular mechanisms underlying cognitive deficits. Ultimately, this injection model not only advances our knowledge of early pathological events in AD but also paves a way for the development of potential therapeutic interventions to improve memory impairments during the initial stages of AD.

Author Contributions

Conceptualization, M.-K.-W.-M.; writing—original draft preparation, M.-K.-W.-M.; writing—review and editing, D.M.; visualization, M.-K.-W.-M. and D.M.; supervision, D.M.; funding acquisition, D.M. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by Grants-in-Aid for Scientific Research C (D.M. Grant No. 23K06348) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This project was also supported by the YU AI project of the Center for Information and Data Science Education, and JST SPRING, Grant Number JPMJSP2111.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AβAmyloid beta
ADAlzheimer’s disease
AMPARα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
APAction potential
APPAmyloid precursor protein
CA1Cornu ammonis 1
DGDentate gyrus
ECEntorhinal cortex
E/I imbalanceExcitatory/inhibitory imbalance
GABAARγ-aminobutyric acid receptor
HFSHigh-frequency stimulation
IA taskInhibitory avoidance task
Kv channelVoltage-gated potassium channel
LECLateral entorhinal cortex
LTDLong-term depression
LTPLong-term potentiation
MECMedial entorhinal cortex
Nav channelVoltage-gated sodium channel
NFTNeurofibrillary tangle
NMDAN-methyl-D-aspartate
PNPyramidal neuron
PPPerforant path
PSPresenilin
SCSchaffer collateral
TATemporo-ammonic

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Figure 1. Schematic diagrams illustrating the hippocampal circuit and functional heterogeneity along the anatomical axes. (A) The circuit diagram of hippocampal CA1 region. The classical hippocampal circuit comprises indirect and direct inputs from EC Layer II and III, via the SC and TA pathways, to CA1 which sends projection back to the EC Layer V. The indirect and direct pathways converge at the proximal and distal apical dendrites of CA1 PN, respectively (upper panel). CA1 integrates non-spatial information from LEC and spatial information from MEC and provides the primary output of the hippocampus, along with subiculum (lower panel). (B) Functional heterogeneity of CA1 across the longitudinal, transverse and radial axes. The left panel illustrates that dorsal CA1 is particularly engaged in spatial/contextual memory whereas ventral CA1 mediates social-related cues. The upper right panel shows that proximal CA1 exhibits specific firing towards spatial information whereas distal CA1 PNs are more responsive to object encoding. The lower right panel represents that deep CA1 PNs are highly activated during spatial encoding whilst superficial neurons are specialized for processing of non-spatial information. CA, cornu ammonis; DG, dentate gyrus; EC, entorhinal cortex; LEC, lateral entorhinal cortex; MEC, medial entorhinal cortex; PN, pyramidal neuron; SC, Schaffer collateral; Sub, subiculum; TA, temporo-ammonic.
Figure 1. Schematic diagrams illustrating the hippocampal circuit and functional heterogeneity along the anatomical axes. (A) The circuit diagram of hippocampal CA1 region. The classical hippocampal circuit comprises indirect and direct inputs from EC Layer II and III, via the SC and TA pathways, to CA1 which sends projection back to the EC Layer V. The indirect and direct pathways converge at the proximal and distal apical dendrites of CA1 PN, respectively (upper panel). CA1 integrates non-spatial information from LEC and spatial information from MEC and provides the primary output of the hippocampus, along with subiculum (lower panel). (B) Functional heterogeneity of CA1 across the longitudinal, transverse and radial axes. The left panel illustrates that dorsal CA1 is particularly engaged in spatial/contextual memory whereas ventral CA1 mediates social-related cues. The upper right panel shows that proximal CA1 exhibits specific firing towards spatial information whereas distal CA1 PNs are more responsive to object encoding. The lower right panel represents that deep CA1 PNs are highly activated during spatial encoding whilst superficial neurons are specialized for processing of non-spatial information. CA, cornu ammonis; DG, dentate gyrus; EC, entorhinal cortex; LEC, lateral entorhinal cortex; MEC, medial entorhinal cortex; PN, pyramidal neuron; SC, Schaffer collateral; Sub, subiculum; TA, temporo-ammonic.
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Figure 2. Schematic diagrams illustrating the input–output function and topographical heterogeneity of CA1 along its anatomical axes. (A) The input–output function of CA1 PN. A neuron receives information via the synapse and integrates it at the soma. Its intrinsic properties determine the likelihood of firing AP, thus serving as a crucial link between synaptic input and AP output. Intrinsic excitability can be modulated by passive and active membrane properties, including voltage-gated ion channels. Glutamatergic transmission can be modified via either pre-synaptic glutamate release or post-synaptic glutamate receptor expression. Though controlled by independent mechanisms, both forms of plasticity are tightly coupled and bi-directionally adjusted so that neuronal activity is maintained to prevent extreme changes. (B) Intrinsic and synaptic heterogeneity of CA1 across the longitudinal axis. Dorsal CA1 PNs display a stronger and more stable synaptic plasticity but are less excitable than its counterpart cells. (C) Intrinsic and synaptic heterogeneity of CA1 across the transverse axis. In the dorsal hippocampus, similar synaptic properties are found at proximal and distal CA1 PNs together with equivalent excitability whereas CA1b is distinguished by having lower intrinsic excitability with higher synaptic integrating properties. (D) Intrinsic and synaptic heterogeneity of CA1 across the radial axis. Synaptic plasticity of CA1 PNs is more robust in the superficial layer whereas deep CA1 PNs are capable of eliciting higher firing. AP, action potential; CA, cornu ammonis; D, dorsal; Kv channel, voltage-gated potassium channel; Nav, voltage-gated sodium channel; PN, pyramidal neuron; Sup, superficial; V, ventral.
Figure 2. Schematic diagrams illustrating the input–output function and topographical heterogeneity of CA1 along its anatomical axes. (A) The input–output function of CA1 PN. A neuron receives information via the synapse and integrates it at the soma. Its intrinsic properties determine the likelihood of firing AP, thus serving as a crucial link between synaptic input and AP output. Intrinsic excitability can be modulated by passive and active membrane properties, including voltage-gated ion channels. Glutamatergic transmission can be modified via either pre-synaptic glutamate release or post-synaptic glutamate receptor expression. Though controlled by independent mechanisms, both forms of plasticity are tightly coupled and bi-directionally adjusted so that neuronal activity is maintained to prevent extreme changes. (B) Intrinsic and synaptic heterogeneity of CA1 across the longitudinal axis. Dorsal CA1 PNs display a stronger and more stable synaptic plasticity but are less excitable than its counterpart cells. (C) Intrinsic and synaptic heterogeneity of CA1 across the transverse axis. In the dorsal hippocampus, similar synaptic properties are found at proximal and distal CA1 PNs together with equivalent excitability whereas CA1b is distinguished by having lower intrinsic excitability with higher synaptic integrating properties. (D) Intrinsic and synaptic heterogeneity of CA1 across the radial axis. Synaptic plasticity of CA1 PNs is more robust in the superficial layer whereas deep CA1 PNs are capable of eliciting higher firing. AP, action potential; CA, cornu ammonis; D, dorsal; Kv channel, voltage-gated potassium channel; Nav, voltage-gated sodium channel; PN, pyramidal neuron; Sup, superficial; V, ventral.
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Figure 3. Effect of Aβ1-42 oligomers on inhibitory avoidance (IA) task. On the training day, the rats were placed in the safe side of the IA box facing opposite the trap door. When the door was opened, they entered the dark side of the box at will. Four seconds after their entry, the door was closed and a brief electrical foot shock (1.6 mA, 2 s) was applied. The rats were kept in the dark compartment for 10 s with the door closed and returned to their home cage. After 30 min, they were placed in the light compartment and allowed to enter after the door was opened. No foot shock was delivered during this time. The prolonged latency to enter the light compartment after shock indicates formation of contextual memory. The details of the experimental procedure can be found in [47,48,49]. Though unilateral injection (red circle showing dorsal CA1) did not affect learning performance (upper panel), a shorter latency was observed after bilateral injection of Aβ1-42 oligomers into the dorsal CA1 (lower panel).
Figure 3. Effect of Aβ1-42 oligomers on inhibitory avoidance (IA) task. On the training day, the rats were placed in the safe side of the IA box facing opposite the trap door. When the door was opened, they entered the dark side of the box at will. Four seconds after their entry, the door was closed and a brief electrical foot shock (1.6 mA, 2 s) was applied. The rats were kept in the dark compartment for 10 s with the door closed and returned to their home cage. After 30 min, they were placed in the light compartment and allowed to enter after the door was opened. No foot shock was delivered during this time. The prolonged latency to enter the light compartment after shock indicates formation of contextual memory. The details of the experimental procedure can be found in [47,48,49]. Though unilateral injection (red circle showing dorsal CA1) did not affect learning performance (upper panel), a shorter latency was observed after bilateral injection of Aβ1-42 oligomers into the dorsal CA1 (lower panel).
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Min-Kaung-Wint-Mon; Mitsushima, D. Aβ1-42 Oligomer Injection Model: Understanding Neural Dysfunction and Contextual Memory Deficits in Dorsal CA1. J. Dement. Alzheimer's Dis. 2025, 2, 25. https://doi.org/10.3390/jdad2030025

AMA Style

Min-Kaung-Wint-Mon, Mitsushima D. Aβ1-42 Oligomer Injection Model: Understanding Neural Dysfunction and Contextual Memory Deficits in Dorsal CA1. Journal of Dementia and Alzheimer's Disease. 2025; 2(3):25. https://doi.org/10.3390/jdad2030025

Chicago/Turabian Style

Min-Kaung-Wint-Mon, and Dai Mitsushima. 2025. "Aβ1-42 Oligomer Injection Model: Understanding Neural Dysfunction and Contextual Memory Deficits in Dorsal CA1" Journal of Dementia and Alzheimer's Disease 2, no. 3: 25. https://doi.org/10.3390/jdad2030025

APA Style

Min-Kaung-Wint-Mon, & Mitsushima, D. (2025). Aβ1-42 Oligomer Injection Model: Understanding Neural Dysfunction and Contextual Memory Deficits in Dorsal CA1. Journal of Dementia and Alzheimer's Disease, 2(3), 25. https://doi.org/10.3390/jdad2030025

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