Ammon’s Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration

Pang, Cindy C C; Kiecker, Clemens; O’Brien, John; Noble, Wendy; Chang, Raymond Chuen‐Chung

doi:10.1177/1073858418778747

Cited by 45 publications

(24 citation statements)

References 120 publications

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“…On top of these expected behavioral changes, we addressed novel readouts of social behavior, suspected to reflect CA2/CA3 destruction in our model, and known to play a role in human viral encephalitis [ 4 , 35 ]. We tested in the 3 × tamoxifen mice social recognition memory, employing our recently developed SocioBox, and combined it with thermography (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis

Wilke

Hindermann

Moussavi

et al. 2021

acta neuropathol commun

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Up to one person in a population of 10,000 is diagnosed once in lifetime with an encephalitis, in 50–70% of unknown origin. Recognized causes amount to 20–50% viral infections. Approximately one third of affected subjects develops moderate and severe subsequent damage. Several neurotropic viruses can directly infect pyramidal neurons and induce neuronal death in cortex and hippocampus. The resulting encephalitic syndromes are frequently associated with cognitive deterioration and dementia, but involve numerous parallel and downstream cellular and molecular events that make the interpretation of direct consequences of sudden pyramidal neuronal loss difficult. This, however, would be pivotal for understanding how neuroinflammatory processes initiate the development of neurodegeneration, and thus for targeted prophylactic and therapeutic interventions. Here we utilized adult male NexCreERT2xRosa26-eGFP-DTA (= ‘DTA’) mice for the induction of a sterile encephalitis by diphtheria toxin-mediated ablation of cortical and hippocampal pyramidal neurons which also recruits immune cells into gray matter. We report multifaceted aftereffects of this defined process, including the expected pathology of classical hippocampal behaviors, evaluated in Morris water maze, but also of (pre)frontal circuit function, assessed by prepulse inhibition. Importantly, we modelled in encephalitis mice novel translationally relevant sequelae, namely altered social interaction/cognition, accompanied by compromised thermoreaction to social stimuli as convenient readout of parallel autonomic nervous system (dys)function. High resolution magnetic resonance imaging disclosed distinct abnormalities in brain dimensions, including cortical and hippocampal layering, as well as of cerebral blood flow and volume. Fluorescent tracer injection, immunohistochemistry and brain flow cytometry revealed persistent blood–brain-barrier perturbance and chronic brain inflammation. Surprisingly, blood flow cytometry showed no abnormalities in circulating major immune cell subsets and plasma high-mobility group box 1 (HMGB1) as proinflammatory marker remained unchanged. The present experimental work, analyzing multidimensional outcomes of direct pyramidal neuronal loss, will open new avenues for urgently needed encephalitis research.

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Section: Resultsmentioning

confidence: 99%

Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis

Wilke

Hindermann

Moussavi

et al. 2021

acta neuropathol commun

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“…Additionally, whether differential gene expression in the neuronal populations might result in a poor ability of CA3 neurons to take up aggregated α-syn species at their terminals is unknown. Furthermore, a recent review points toward the CA2 subregion of the hippocampus, located in-between CA3 and CA1, as an underrated area in PD and related disorders [64]. The CA2 pyramidal neurons display distinctive characteristics regarding both protein expression and physiology, including synaptic function, and might thus play an important role in the spreading of pathology – or lack thereof – between hippocampal subregions [64].…”

Section: Discussionmentioning

confidence: 99%

Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates

Elfarrash

Jensen

Ferreira

et al. 2019

acta neuropathol commun

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Here we describe the use of an organotypic hippocampal slice model for studying α-synuclein aggregation and inter-neuronal spreading initiated by microinjection of pre-formed α-synuclein fibrils (PFFs). PFF injection at dentate gyrus (DG) templates the formation of endogenous α-synuclein aggregates in axons and cell bodies of this region that spread to CA3 and CA1 regions. Aggregates are insoluble and phosphorylated at serine-129, recapitulating Lewy pathology features found in Parkinson’s disease and other synucleinopathies. The model was found to favor anterograde spreading of the aggregates. Furthermore, it allowed development of slices expressing only serine-129 phosphorylation-deficient human α-synuclein (S129G) using an adeno-associated viral (AAV) vector in α-synuclein knockout slices. The processes of aggregation and spreading of α-synuclein were thereby shown to be independent of phosphorylation at serine-129. We provide methods and highlight crucial steps for PFF microinjection and characterization of aggregate formation and spreading. Slices derived from genetically engineered mice or manipulated using viral vectors allow testing of hypotheses on mechanisms involved in the formation of α-synuclein aggregates and their prion-like spreading.

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“…The results of a study of a mouse model expressing mutant β-synuclein (linked to DLB) suggested that the pseudo-immaturity of DG granule cells may be a shared endophenotype in patients with neurodegenerative disorders ( Hagihara et al, 2018 ). Several groups have found that hippocampal atrophy is less severe in DLB than AD ( Firbank et al, 2010 ; Elder et al, 2017 ; Pang et al, 2018 ). For instance, Firbank et al (2010) found that the CA1 and subiculum exhibited less atrophy in DLB patients compared to AD patients.…”

Section: Introductionmentioning

confidence: 99%

The Volume of Hippocampal Subfields in Relation to Decline of Memory Recall Across the Adult Lifespan

Zheng

Cui

Zhang

et al. 2018

Front. Aging Neurosci.

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Background: The hippocampus is an important limbic structure closely related to memory function. However, few studies have focused on the association between hippocampal subfields and age-related memory decline. We investigated the volume alterations of hippocampal subfields at different ages and assessed the correlations with Immediate and Delayed recall abilities.Materials and Methods: A total of 275 participants aged 20–89 years were classified into 4 groups: Young, 20–35 years; Middle-early, 36–50 years; Middle-late, 51–65 years; Old, 66–89 years. All data were acquired from the Dallas Lifespan Brain Study (DLBS). The volumes of hippocampal subfields were obtained using Freesurfer software. Analysis of covariance (ANCOVA) was performed to analyze alterations of subfield volumes among the 4 groups, and multiple comparisons between groups were performed using the Bonferroni method. Spearman correlation with false discovery rate correction was used to investigate the relationship between memory recall scores and hippocampal subfield volumes.Results: Apart from no significant difference in the left parasubiculum (P = 0.269) and a slight difference in the right parasubiculum (P = 0.022), the volumes of other hippocampal subfields were significantly different across the adult lifespan (P < 0.001). The hippocampal fissure volume was increased in the Old group, while volumes for other subfields decreased. In addition, Immediate recall scores were associated with volumes of the bilateral molecular layer, granule cell layer of the dentate gyrus (GC-DG), cornus ammonis (CA) 1, CA2/3, CA4, left fimbria and hippocampal amygdala transition area (HATA), and right fissure (P < 0.05). Delayed recall scores were associated with the bilateral molecular layer, GC-DG, CA2/3 and CA4; left tail, presubiculum, CA1, subiculum, fimbria and HATA (P < 0.05).Conclusion: The parasubiculum volume was not significantly different across the adult lifespan, while atrophy in dementia patients in some studies. Based on these findings, we speculate that volume changes in this region might be considered as a biomarker for dementia disorders. Additionally, several hippocampal subfield volumes were significantly associated with memory scores, further highlighting the key role of the hippocampus in age-related memory decline. These regions could be used to assess the risk of memory decline across the adult lifespan.

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Ammon’s Horn 2 (CA2) of the Hippocampus: A Long-Known Region with a New Potential Role in Neurodegeneration

Cited by 45 publications

References 120 publications

Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis

Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis

Organotypic slice culture model demonstrates inter-neuronal spreading of alpha-synuclein aggregates

The Volume of Hippocampal Subfields in Relation to Decline of Memory Recall Across the Adult Lifespan

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