Involvement of cellular metabolism in age-related LTP modifications in rat hippocampal slices

Abstract

Recent studies emphasized crucial role of astrocytic glycogen metabolism in regulation of synaptic transmission and plasticity in young animals. However, the interplay between age-related synaptic plasticity impairments and changes in energetic metabolism remains obscure. To address this issue, we investigated, in hippocampal slices of young (one month) and aged rats (20-22-months), the impact of glycogen degradation inhibition on LTP, mRNA expression for glycogen metabolism enzymes and morphology of dendritic spines. We show that, whereas in young hippocampi, inhibition of glycogen phosphorolysis disrupts the late phase of LTP in the Schaffer collateral-CA1 pathway, in aged rats, blockade of glycogen phosphorylase tends to enhance it. Gene expression for key energy metabolism enzymes, such as glycogen synthase and phosphorylase and glutamine synthetase showed marked differences between young and aged groups and changes in expression of these enzymes preceded plasticity phenomena. Interestingly, in the aged group, a prominent expression of these enzymes was found also in neurons. Concluding, we show that LTP in the considered pathway is differentially modulated by metabolic processes in young and aging animals, indicating a novel venue of studies aiming at preventing cognitive decline during aging.

Aging‐associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte‐to‐neuron lactate shuttle

“…While in young animals, it was present predominantly in putative astrocytes (Figure a,c), in middle‐aged mice, it was located both in astrocytes and in neurons (Figure b,c). Our previous studies have shown that inhibition of glycogen breakdown in astrocytes had an opposite effect on the LTP magnitude in young and middle‐aged rats: in the young group it disrupted LTP maintenance whereas in the aged one it appeared to favor LTP formation (Drulis‐Fajdasz, ). Therefore, we conclude that the capability to synthesize and degrade glycogen is higher in hippocampi of middle‐aged than young mice (Figure c; Figure a–c; Supporting Information, Table S5).…”

“…In contrast, just recently, we have demonstrated that the inhibition of glycogen breakdown in astrocytes of old animals significantly elevates LTP magnitude in hippocampal slices and affects the mode of dendritic spines maturation (Drulis‐Fajdasz et al, ). In other words, inhibition of glycogen degradation in hippocampi of old animals prevents aging‐associated defects in memory formation.…”

“…We also observed aging‐associated relocation of Pygb, a regulator of glycogen degradation, and Pgm1, the enzyme directing glucose to glycogen synthesis, to neurons. Previously, we have demonstrated that in contrast to young rats, the inhibition of glycogen degradation in old animals improves neuronal plasticity and reverts aging‐associated changes in LTP formation (Drulis‐Fajdasz, ). This have led us to made an assumption that the increased level/activity of Pygb in neurons of hippocampi is the main cause of aging‐associated decline in memory formation.…”

Ketamine administered pregnant rats impair learning and memory in offspring via the CREB pathway

“…Won demonstrated that DA-9801 exerts its beneficial effects of stimulating neurite outgrowth through the ERK1/2-CREB pathway in PC12 cells [48]. Behavioral analyses of animals with altered ERK signaling have revealed a central involvement of this cascade in learning and memory [49], and it has been reported that ERK activity was decreased in dentate gyrus of aged rats, which did not sustain LTP [50, 51]. Coccomyxa gloeobotrydiformis (CGD) significantly increased ERK and CREB phosphorylation in the hippocampus, suggesting that the learning and memory-enhancing effects of CGD might be associated with the ERK/CREB pathway [52].…”

Does shuttling of glycogen‐derived lactate from astrocytes to neurons take place during neurotransmission and memory consolidation?

“…For example, knockout (KO) of brain glycogen synthase impairs hippocampal long‐term potentiation (LTP) and memory consolidation, clearly proving a major role for glycogen in cognitive activities (Duran, Saez, Gruart, Guinovart, & Delgado‐Garcia, ). This conclusion is supported by studies in which inhibition of glycogen phosphorylase in cultured cells, brain slices, or in living brain with different compounds (e.g., 1,4‐dideoxy‐1,4‐imino‐D‐arabinitol (DAB), [R‐R*,S*]‐5‐chloro‐N‐[2‐hydroxy‐3‐(methoxymethylamino)‐3‐oxo‐1‐(phenylmethyl)propyl]‐1H‐indole‐2‐carboxamide (CP‐316,819), isofagomine, 4‐(2‐chlorophenyl)‐1‐ethyl‐1,4‐dihydro‐6‐methyl‐2,3,5‐pyridinetricarboxylic acid (BAY U6751)) also has deleterious effects on glutamatergic neurotransmission, LTP, memory consolidation, and other aspects of neural function (e.g., Drulis‐Fajdasz et al, ; Hertz & Gibbs, ; Mozrzymas, Szczęsny, & Rakus, ; Sickmann, Walls, Schousboe, Bouman, & Waagepetersen, ; Suzuki et al, ; Zhang et al, ). Most of the brain glycogen is contained in astrocytes, and there may be a tendency to ascribe the effects of glycogenolysis impairment to astrocytes.…”