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Developmental Aspects of Glucose and Calcium Availability on the Persistence of Memory Function Over the Lifespan

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Developmental Aspects of Glucose and Calcium Availability on the Persistence of Memory Function Over the Lifespan

Matthew R Holahan et al. Front Aging Neurosci.

Abstract

An important aspect concerning the underlying nature of memory function is an understanding of how memories are acquired and lost. The stability, and ultimate demise, of memory over the lifespan of an organism remains a critical topic in determining the neurobiological mechanisms that mediate memory representations. This has important implications for the elucidation and treatment of neurodegenerative diseases such as Alzheimer's disease (AD). One important question in the context of preserving functional plasticity over the lifespan is the determination of the neurobiological structural and functional changes that contribute to the formation of memory during the juvenile time frame that might provide protection against later memory dysfunction by promoting the establishment of redundant neural pathways. The main question being, if memory formation during the juvenile period does strengthen and preserve memory stability over the lifespan, what are the neurobiological structural or functional substrates that mediate this effect? One neural attribute whose function may be altered with early life experience and provide a mechanism to preserve memory through the lifespan is glucose transport-linked calcium (Ca2+) buffering. Because peak increases in glucose utilization overlap with a timeframe during which spatial training can enhance later memory processing, it might be the case that learning-associated changes in glucose utilization would provide an important neural functional change to preserve memory function throughout the lifespan. The glucose transporters are proteins that are reduced in AD pathology and there is evidence that glucose reductions can impair Ca2+ buffering. In the absence of an appropriate supply of ATP, provided via glucose transport and glycolysis, Ca2+ levels can rise leading to neural vulnerability with ensuing pathological outcomes. In this review, we explore the hypothesis that enhancing glucose utilization with spatial training during the preadolescent period will provide a functional enhancement that regulates glucose-dependent Ca2+ signaling during aging or neurodegeneration and provide essential neural resources to preserve functional plasticity and memory function.

Keywords: aging; calcium; childhood; early life experience; energetic metabolism; glucose; memory; neurodegeneration.

Figures

FIGURE 1
FIGURE 1
Examples of spatial tasks used to assess allocentric processing in humans. (A) An example of a circular arena using indirect cues to locate a goal. In the indirect test, the target object (bear in figure) remains at a fixed location in relation to the indirect cues (images on the walls). The indirect cues provide information as to where the target object is located but no one cue indicates the precise location of the object. (B) Screen shots from the Memory Island Navigation Task (open access from https://openi.nlm.nih.gov/detailedresult?img=PMC3906800_abn_122_4_1189_fig1a&req=4). For this task, subjects complete both visible (A) and hidden trials (B). In the visible condition, target items (C–F) are marked by large flags, which can be seen from far away. In the hidden condition, no flag markers are present and subjects are required to locate the same target object (D) on each trial (the location is identical to the visible trial). The hidden trials test for allocentric/spatial learning.
FIGURE 2
FIGURE 2
Examples of spatial tasks used to asses allocentric processing in rodents. (A) The water maze task. The basic procedure consists of placing a rodent (mouse or rat) into a large circular pool filled with opaque water. In the spatial version, the animal is required to swim to a platform that is slightly submerged under the water making it hidden from view. The rodent locates the platform (and remembers its location) by using various cues placed around the room (indirect cues). (B) For the object in a novel location spatial task, rats are individually placed into an arena and allowed to explore. Two objects are placed in different quadrants and remain in the same location for the training phase. At some time delay after training, rats are tested whereby one of the objects is moved to a different quadrant of the arena. This procedure takes advantage of a rats spontaneous tendency to explore objects that have changed location within an otherwise stable environment.
FIGURE 3
FIGURE 3
Human-rat comparison of developmental emergence of spatial-allocentric ability. Data from the human (A) and rat (B) studies (Table 2) were used to illustrate the developmental time when spatial memory function emerged in both species. Data from each paper from the youngest age group included in the study were used as the baseline value. These values were converted to 100%. From that, the change from baseline for each of the ages as reported in the studies up to the oldest age groups was determined. The red line indicates asymptotic performance as reported in the studies and from this value, the half maximal value (50% of asymptotic performance – dashed purple line) was calculated to determine the age at which allocentric-spatial learning emerges. Allocentric processing appears to emerge in 11/12-year-old humans (A) and spatial processing appears to emerge in rats (B) at PND20/PND21 (green arrows).
FIGURE 4
FIGURE 4
Cellular and molecular changes involved in synaptic plasticity. The figure illustrates numerous mechanisms that could be involved in synaptic plasticity. Special attention is given to Ca2+, as its increase can trigger either the LTP or LTD occurrence with evident intracellular signaling cascade. On the post-synaptic site, the illustrated receptor are NMDA and the silent receptors are AMPA. NMDA receptor: N-methyl-D-aspartate receptor; AMPA receptor: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; VGCC: voltage-gated calcium channels; CaMKII: calcium/calmodulin-dependent protein kinase type II; CaN: calcineurin; PKC: protein kinase C, PKM: protein kinase M.
FIGURE 5
FIGURE 5
Intracellular calcium dynamics to induce LTP/LTD. Several factors related to Ca2+ dynamics influence long-term changes in synapses, strengthening or weakening the transmission of information in this structure. LTP or LTD are influenced by the amplitude, duration and location of calcium signaling. Variations in these factors allow different paradigms that may explain how the same signaling element may lead to different cellular and molecular responses. NMDA receptor: N-methyl-D-aspartate receptor; VGCC: voltage-gated calcium channels.
FIGURE 6
FIGURE 6
Glucose-regulation of Calcium. In the physiological situation, glucose is mainly transported by glucose transporters (GLUTs) located in the neuronal plasma membrane. The glucose is then converted to ATP by glycolysis and tricarboxylic acid cycle (TCA). The produced ATP will serve as a substrate for two ATPases, SERCA and PMCA, which pump Ca2+ into the endoplasmic reticulum and out of the cell, respectively. Ca2+ has its influx into the cytoplasm by various cellular mechanisms, however only VGCC (voltage-gated calcium channel) and NMDA (N-methyl-D-aspartate) receptors are represented by their importance to LTP/LTD. Changes in the glucose transport or metabolism by the neuron are expected to impact ATP-dependent mechanisms leading to intracellular Ca2+ deregulation. SR: sarcoplasmic reticulum; PMCA: plasma membrane Ca2+-ATPase; SERCA: sarco/endoplasmic reticulum Ca2+-ATPase; Gly: glycolysis; ATP: adenosine triphosphate.

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