Synaptic plasticity in early aging

Abstract

Studies of how aging affects brain plasticity have largely focused on old animals. However, deterioration of memory begins well in advance of old age in animals, including humans; the present review is concerned with the possibility that changes in synaptic plasticity, as found in the long-term potentiation (LTP) effect, are responsible for this. Recent results indicate that impairments to LTP are in fact present by early middle age in rats but only in certain dendritic domains. The search for the origins of these early aging effects necessarily involves ongoing analyses of how LTP is induced, expressed, and stabilized. Such work points to the conclusion that cellular mechanisms responsible for LTP are redundant and modulated both positively and negatively by factors released during induction of potentiation. Tests for causes of the localized failure of LTP during early aging suggest that the problem lies in excessive activity of a negative modulator. The view of LTP as having redundant and modulated substrates also suggests a number of approaches for reversing age-related losses. Particular attention will be given to the idea that induction of brain-derived neurotrophic factor, an extremely potent positive modulator, can be used to provide long periods of normal plasticity with very brief pharmacological interventions. The review concludes with a consideration of how the selective, regional deficits in LTP found in early middle age might be related to the global phenomenon of brain aging. #

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

“…The middle-age period was chosen because it increasingly appears to be an important window of time at which to initiate interventions designed to preserve cognitive function into the geriatric period. At midlife, subtle cognitive impairments begin to appear, along with structural and genomic changes associated with brain aging (31)(32)(33)(34). Our results show that higher than normal dietary VitD3 may improve the chances of successful brain aging and that changes in neuronal synaptic function in the hippocampus may underlie its protective effects against age-related cognitive decline.…”

“…A common feature of brain aging is a decrease in synaptic strength or impaired communication between neurons (32,44,(55)(56)(57)(58). Synaptic connections become dysfunctional, perhaps in part as a result of reduced vesicle trafficking and neurotransmitter release, causing diminished plasticity (56,(59)(60)(61).…”

“…Further, because of its more complex nature, reversal learning may be viewed as a task of executive function (51,52). The middle-age period is often characterized by the onset of such subtle changes in cognitive performance, most notably in executive function and processing speed (32,53,54). We initially assessed spatial reference memory, where rats were trained to locate a hidden platform in a specific location, and found no significant differences among groups of middle-aged animals treated with varying levels of vitamin D. During spatial reversal, however, the animals were required to learn a new platform location in a single day and then to remember the new location after several days.…”

Spatial reference and working memory across the lifespan of male Fischer 344 rats

“…Dysfunction of this system and concomitant loss of associated learning and memory functions are well-documented at advanced ages. Indeed, both reference memory (memory for information that is held constant over time) and working memory (the ability to remember, usually for a relatively brief period of time, information that must be distinguished from previously learned similar information) are adversely affected during the aging process [17,[25][26][27]29,32,34,36]. Importantly, such impairments in medial temporal lobe functioning are not an inevitable consequence of the aging process [5,7,19,45].…”

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

“…The mechanisms by which 5-HT6R antagonists can counteract age-related deficits in memory processes are yet unknown. One can however hypothesize a withdrawal of the inhibition exerted by serotonin onto the cholinergic system, notably in the 5-HT6R blockade improves memory V Da Silva Costa et al hippocampus (Foley et al, 2004;Lieben et al, 2005;PerezGarcia and Meneses, 2005;Riemer et al, 2003;ShiraziSouthall et al, 2002)Fthis latter being largely altered during aging (Buhot et al, 2000;Decker and McGaugh, 1991;McEntee and Crook, 1992)Fand/or an interaction with the hippocampal glutamatergic system, leading to an increase in synaptic plasticity (eg long-term potentiation; Bliss and Collingridge, 1993;Dawson et al, 2000Dawson et al, , 2001Foster, 1999;Lynch et al, 2006;Morris, 2006), which is altered during aging (see for review Lynch et al, 2006). Other concepts have been recently proposed (see Perez-Garcia and Meneses, 2008).…”