Retrograde Amnesia - A Question of Disturbed Calcium Levels?

Abstract

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.

Keywords: PMCA; associative memory; dementia; memory loss; neuroplastin; post-traumatic stress disorder (PTSD); retrograde amnesia.

FIGURE 1

(A) The neuroplastin gene is localized on chromosome 9 in the mouse. It has a size of approximately 76 kb. By homologous recombination in embryonic stem cells, a floxed neuroplastin allele was generated in which the first exon encoding the start codon ATG and the signal sequence is surrounded by lox recognition sequences for the Cre recombinase (Bhattacharya et al., 2017). Cre recombinase activity leads to deletion of the first exon generating a neuroplastin null allele. By use of different Cre recombinases (constitutive, conditional, and/or inducible) the neuroplastin allele can be inactivated in vivo in all cells, in specific cell types, and/or in specific cell types at a chosen time point. (B) Neuroplastin (blue) is expressed as 55 kD isoform containing 2 Ig domains or as the brain specific 65 kD isoform containing 3 Ig domains. Both isoforms may contain the intracellular DDEP amino acid motif resulting from alternative splicing. Complex formation of neuroplastin with PMCA results in efficient Ca²⁺ extrusion from the cell. In the absence of neuroplastin, the amount of PMCAs rapidly decreases. (C) Summary of abnormalities detected by various behavioral paradigms in neuroplastin mutants. Green boxes: performance like control; red boxes: performance negatively affected by the mutation; blue boxes: performance improved by the mutation; white boxes: not determined. (D) The time schedule for the assessment of learning and memory using different neuroplastin mutants. Note that retrograde amnesia can be induced when training occurs before inactivation of the neuroplastin gene.