Emerging Views and Players in Neuronal Calcium Signaling: Synaptic Plasticity, Learning/Memory, Aging and Neuroinflammation

Introduction: Neuronal Ca²⁺ signals generated through the activation of Ca²⁺-induced Ca²⁺ release in response to activity-generated Ca²⁺ influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca²⁺ release channels in rat primary hippocampal neuronal cells or hippocampal tissue.

Methods and Results: Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca²⁺ release channels in rat hippocampal slices. Suppression of RyR channel activity (1 h preincubation with 20 μM ryanodine) abolished both LTP induction and the enhanced expression of these channels; it also promoted an increase in the surface expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1 and GluR2 and caused a moderate but significant reduction of dendritic spine density. In addition, training rats in the Morris water maze induced memory consolidation, which lasted for several days after the end of the training period, accompanied by an increase in the mRNA levels and the protein content of the RyR2 channel isoform.

Discussion: We confirm in this work that LTP induction by TBS protocols requires functional RyR channels. We propose that the increments in the protein content of RyR2 Ca²⁺ release channels, induced by LTP or spatial memory training, play a significant role in hippocampal synaptic plasticity and spatial memory consolidation.

Retrograde amnesia is the inability to remember events or information. The successful acquisition and memory of information is required before retrograde amnesia may occur. Often, the trigger for retrograde amnesia is a traumatic event. Loss of memories may be caused in two ways: either by loss/erasure of the memory itself or by the inability to access the memory, which is still present. In general, memories and learning are associated with a positive connotation although the extinction of unpleasant experiences and memories of traumatic events may be highly welcome. In contrast to the many experimental models addressing learning deficits caused by anterograde amnesia, the incapability to acquire new information, retrograde amnesia could so far only be investigated sporadically in human patients and in a limited number of model systems. Apart from models and diseases in which neurodegeneration or dementia like Alzheimer’s disease result in loss of memory, retrograde amnesia can be elicited by various drugs of which alcohol is the most prominent one and exemplifies the non-specific effects and the variable duration. External or internal impacts like traumatic brain injury, stroke, or electroconvulsive treatments may similarly result in variable degrees of retrograde amnesia. In this review, I will discuss a new genetic approach to induce retrograde amnesia in a mouse model and raise the hypothesis that retrograde amnesia is caused by altered intracellular calcium homeostasis. Recently, we observed that neuronal loss of neuroplastin resulted in retrograde amnesia specifically for associative memories. Neuroplastin is tightly linked to the expression of the main Ca²⁺ extruding pumps, the plasma membrane calcium ATPases (PMCAs). Therefore, neuronal loss of neuroplastin may block the retrieval and storage of associative memories by interference with Ca²⁺ signaling cascades. The possibility to elicit retrograde amnesia in a controlled manner allows to investigate the underlying mechanisms and may provide a deeper understanding of the molecular and circuit processes of memory.