Early Presynaptic and Postsynaptic Calcium Signaling Abnormalities Mask Underlying Synaptic Depression in Presymptomatic Alzheimer's Disease Mice

Abstract

Alzheimer’s disease (AD)-linked presenilin mutations result in pronounced endoplasmic reticulum (ER) calcium disruptions that occur prior to detectable histopathology and cognitive deficits. More subtly, these early AD-linked calcium alterations also reset neurophysiological homeostasis, such that calcium-dependent pre- and postsynaptic signaling appear functionally normal yet are actually operating under aberrant calcium signaling systems. In these 3xTg-AD mouse brains, upregulated RyR activity is associated with a shift towards synaptic depression, likely through a reduction in presynaptic vesicle stores and increased postsynaptic outward currents through SK2 channels. The deviant RyR-calcium involvement in the 3xTg-AD mice also compensates for an intrinsic predisposition for hippocampal LTD and reduced LTP. In this study we detail the impact of disrupted ryanodine receptor (RyR)-mediated calcium stores on synaptic transmission properties, long term depression (LTD) and calcium-activated membrane channels of hippocampal CA1 pyramidal neurons in presymptomatic 3xTg-AD mice. Using electrophysiological recordings in young 3xTg-AD and NonTg hippocampal slices, we show that increased RyR-evoked calcium release in 3xTg-AD mice ‘normalizes’ an altered synaptic transmission system operating under a shifted homeostatic state that is not present in NonTg mice. In the process, we uncover compensatory signaling mechanisms recruited early in the disease process which counterbalance the disrupted RyR-calcium dynamics, namely increases in presynaptic spontaneous vesicle release, altered probability of vesicle release, and upregulated postsynaptic SK channel activity. As AD is increasingly recognized as a ‘synaptic disease’, calcium-mediated signaling alterations may serve as a proximal trigger for the synaptic degradation driving the cognitive loss in AD.

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…Our study revealed significant reductions in the number of dendritic spines in the hippocampus of 3xTg‐AD mice, suggesting that these mice have early defects in synaptic processing and neuronal communication in a brain region that is critical for learning and memory. Similar to our findings, other AD transgenic models also show reduced numbers of dendritic spines at early ages in the hippocampus, although the mechanism responsible for these dendritic spine alterations remains elusive (Chakroborty et al., 2012; Clark et al., 2015; Du et al., 2010; Jacobsen et al., 2006; Mueller et al., 2010). In addition, we also found that 3xTg‐AD mice display an increase in long immature‐type dendritic spines.…”

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

“…To our knowledge, the present work is the first to demonstrate that icv-STZ reduces the hippocampalprefrontal LTP in vivo with no significant effects on the short-term synaptic plasticity. Synaptic dysfunctions in animal models of Alzheimer's disease have been well addressed in transgenic models (Chakroborty et al, 2012;Sancheti et al, 2013;Clark et al, 2015). Additionally, Xu et al (2014) have reported that icv-STZ decreases the dendritic spine density, which was in turn associated with alterations in spatial memory and hippocampal LTP in vitro.…”

Propagation of Neuronal Damage to Embryonic Grafts Transplanted in the Hippocampus of Murine Models of Alzheimer's Disease

“…However, other studies reported exaggerated endoplasmic reticulum Ca 2+ signals, mediated by the ryanodine receptor, in hippocampal neurons of young 3xTg-AD mice (4 months old) compared to age-matched WT animals, resulting in spine and synapse loss in the CA3 and CA1 regions of the hippocampus. [28][29][30] Our experiments provide evidence that the high level of soluble Ab produced in the host may lead to the propagation of pathophysiology AD features to the neighboring healthy tissues by decreasing spine density compared to the control condition. Indeed, several studies reported that elevated levels of soluble Ab contributed to cognitive deficits and synaptic loss in AD patients.…”

“…On the other hand, the results reported here do not rule out other related mechanisms by which the synaptic plasticity could be affected, like the calcium-overload hypothesis supported by several studies. [28][29][30] The inflammatory reaction of the 3xTg-AD and WT hosts against the transplanted tissues was confirmed by the immunohistochemical examination of reactive astrocytes and microglia. The overall density of GFAP-positive astroglial cells inside the grafts did not change significantly, in 39,40 However, we identified some astrocytes displaying evidence for atrophic features in the tissue transplanted within the 3xTg-AD hippocampus.…”