Calcium signaling in individual APP/PS1 mouse dentate gyrus astrocytes increases <i>ex vivo</i> with Aβ pathology and age without affecting astrocyte network activity

Astrocytes are critical for healthy brain function. In Alzheimer’s disease, astrocytes become reactive, which affects their signaling properties. Here, we measured spontaneous calcium transients ex vivo in hippocampal astrocytes in brain slices containing the dentate gyrus of 6‐ (6M) and 9‐month‐old (9M) APPswe/PSEN1dE9 (APP/PS1) mice. We investigated the frequency and duration of calcium transients in relation to aging, amyloid‐β (Aβ) pathology, and the proximity of the astrocyte to Aβ plaques. The 6M APP/PS1 astrocytes showed no change in spontaneous calcium‐transient properties compared to wild‐type (WT) astrocytes. 9M APP/PS1 astrocytes, however, showed more hyperactivity compared to WT, characterized by increased spontaneous calcium transients that were longer in duration. Our data also revealed an effect of aging, as 9M astrocytes overall showed an increase in calcium activity compared to 6M astrocytes. Subsequent calcium‐wave analysis showed an increase in sequential calcium transients (i.e., calcium waves) in 9M astrocytes, suggesting increased network activity ex vivo. Further analysis using null models revealed that this network effect is caused by chance, due to the increased number of spontaneous transients. Our findings show that alterations in calcium signaling in individual hippocampal astrocytes of APP/PS1 mice are subject to both aging and Aβ pathology but these do not lead to a change in astrocyte network activity. These alterations in calcium dynamics of astrocytes may help to understand changes in neuronal physiology leading to cognitive decline and ultimately dementia

Distinct Spatiotemporal Activation Patterns of the Perirhinal-Entorhinal Network in Response to Cortical and Amygdala Input

The perirhinal (PER) and entorhinal cortex (EC) receive input from the agranular insular cortex (AiP) and the subcortical lateral amygdala (LA) and the main output area is the hippocampus. Information transfer through the PER/EC network however, is not always guaranteed. It is hypothesized that this network actively regulates the (sub)cortical activity transfer to the hippocampal network and that the inhibitory system is involved in this function. This study determined the recruitment by the AiP and LA afferents in PER/EC network with the use of voltage sensitive dye (VSD) imaging in horizontal mouse brain slices. Electrical stimulation (500 μA) of the AiP induced activity that gradually propagated predominantly in the rostro-caudal direction: from the PER to the lateral EC (LEC). In the presence of 1 μM of the competitive γ-aminobutyric acid (GABAA) receptor antagonist bicuculline, AiP stimulation recruited the medial EC (MEC) as well. In contrast, LA stimulation (500 μA) only induced activity in the deep layers of the PER. In the presence of bicuculline, the initial population activity in the PER propagated further towards the superficial layers and the EC after a delay. The latency of evoked responses decreased with increasing stimulus intensities (50-500 μA) for both the AiP and LA stimuli. The stimulation threshold for evoking responses in the PER/EC network was higher for the LA than for the AiP. This study showed that the extent of the PER/EC network activation depends on release of inhibition. When GABAA dependent inhibition is reduced, both the AiP and the LA activate spatially overlapping regions, although in a distinct spatiotemporal fashion. It is therefore hypothesized that the inhibitory network regulates excitatory activity from both cortical and subcortical areas that has to be transmitted through the PER/EC network

The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network

Converging evidence suggests that each parahippocampal and hippocampal subregion contributes uniquely to the encoding, consolidation and retrieval of declarative memories, but their precise roles remain elusive. Current functional thinking does not fully incorporate the intricately connected networks that link these subregions, owing to their organizational complexity; however, such detailed anatomical knowledge is of pivotal importance for comprehending the unique functional contribution of each subregion. We have therefore developed an interactive diagram with the aim to display all of the currently known anatomical connections of the rat parahippocampal-hippocampal network. In this Review, we integrate the existing anatomical knowledge into a concise description of this network and discuss the functional implications of some relatively underexposed connections