Deviant Ryanodine Receptor-Mediated Calcium Release Resets Synaptic Homeostasis in Presymptomatic 3xTg-AD Mice

Abstract

Presenilin mutations result in exaggerated endoplasmic reticulum (ER) calcium release in cellular and animal models of Alzheimer's disease (AD). In this study, we examined whether dysregulated ER calcium release in young 3xTg-AD neurons alters synaptic transmission and plasticity mechanisms before the onset of histopathology and cognitive deficits. Using electrophysiological recordings and two-photon calcium imaging in young (6 -8 weeks old) 3xTg-AD and non-transgenic (NonTg) hippocampal slices, we show a marked increase in ryanodine receptor (RyR)-evoked calcium release within synapse-dense regions of CA1 pyramidal neurons. In addition, we uncovered a deviant contribution of presynaptic and postsynaptic ryanodine receptor-sensitive calcium stores to synaptic transmission and plasticity in 3xTg-AD mice that is not present in NonTg mice. As a possible underlying mechanism, the RyR2 isoform was found to be selectively increased more than fivefold in the hippocampus of 3xTg-AD mice relative to the NonTg controls. These novel findings demonstrate that 3xTg-AD CA1 neurons at presymptomatic ages operate under an aberrant, yet seemingly functional, calcium signaling and synaptic transmission system long before AD histopathology onset. These early signaling alterations may underlie the later synaptic breakdown and cognitive deficits characteristic of later stage AD.

Calcium Signaling and Amyloid Toxicity in Alzheimer Disease

“…Although the mechanism is unclear, the neuroprotective effects of dimebon may lie in its ability to inhibit L-type Ca 2ϩ channels and NMDAR and protect against mitochondrial stress (98). Another target, though not yet in clinical trials, is the RyR, an intracellular Ca 2ϩ release channel that is up-regulated in an initially neuroprotective manner in response to A␤ 1-42 exposure (94) and that shows increased expression and Ca 2ϩ flux in certain familial forms of AD (99,100). Given the ubiquity of Ca 2ϩ signaling, a caveat with these approaches is the potential to disrupt normal neuronal function.…”

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

“…[51][52][53] An increased expression of the ryanodine receptor (RYR), particularly the RYR3 isoform, 53 is one cause for this hypersensitivity of the internal release mechanism. 52,[54][55][56] The increase in RYR expression results in a greater sensitivity to Ca 2+ elevations during normal synaptic transmission. 57 In transgenic mice, entry of Ca 2+ through the NMDA receptors triggered a greater release of Ca 2+ from the RYRs in both the dendrites and spines through the process of Ca 2+ -induced Ca 2+ release (CICR).…”

Enhanced ROS Generation Mediated by Alzheimer's Disease Presenilin Regulation of InsP3R Ca2+ Signaling

“…The mechanisms underlying exaggerated ER Ca 2þ release have been ascribed to enhanced loading of the ER lumen (65) due to disruption of a putative Ca 2þ channel function of wild-type PS (54,75) or to enhanced activity of the SERCA Ca 2þ pump (23). Exaggerated Ca 2þ release has also been accounted for by enhanced Ca 2þ liberation from normal stores through ryanodine receptor (RyR) (10,64,71) and inositol trisphosphate receptor (InsP 3 R) (43,68) Ca 2þ release channels. The latter phenotypes have been observed both in vivo (10,65,70,71) and in vitro (17,31,35,42).…”

“…Exaggerated Ca 2þ release has also been accounted for by enhanced Ca 2þ liberation from normal stores through ryanodine receptor (RyR) (10,64,71) and inositol trisphosphate receptor (InsP 3 R) (43,68) Ca 2þ release channels. The latter phenotypes have been observed both in vivo (10,65,70,71) and in vitro (17,31,35,42). Enhanced release from normal stores has been attributed either to enhanced Ca 2þ release channel expression (10,11,36,72) or, in the case of the InsP 3 R, to enhanced activity in response to its ligand InsP 3 (12,13,35).…”

“…The latter phenotypes have been observed both in vivo (10,65,70,71) and in vitro (17,31,35,42). Enhanced release from normal stores has been attributed either to enhanced Ca 2þ release channel expression (10,11,36,72) or, in the case of the InsP 3 R, to enhanced activity in response to its ligand InsP 3 (12,13,35). Regarding the latter, it is notable that enhanced agonistinduced InsP 3 R-mediated Ca 2þ signals have been used diagnostically to identify FAD patient cells (31,35).…”