Edited by: Thomas C. Foster, University of Florida, USA
Reviewed by: Ángel M. Carrión, Universidad Pablo de Olavide de Sevilla, Spain; Thomas C. Foster, University of Florida, USA
*Correspondence: Carol A. Barnes, Evelyn F. McKnight Brain Institute, Life Sciences North Building, room 355, PO Box 245115, University of Arizona, Tucson, AZ 85724-5115, USA. e-mail:
This is an open-access article subject to an exclusive license agreement between the authors and the Frontiers Research Foundation, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.
During aging, many experience a decline in cognitive function that includes memory loss. The encoding of long-term memories depends on new protein synthesis, and this is also reduced during aging. Thus, it is possible that changes in the regulation of protein synthesis contribute to the memory impairments observed in older animals. Several lines of evidence support this hypothesis. For instance, protein synthesis is required for a longer period following learning to establish long-term memory in aged rodents. Also, under some conditions, synaptic activity or pharmacological activation can induce
The idea that changes in the amount of protein synthesis in the brain might explain some of the cognitive effects of aging began to be tested in the 1960s (Flexner et al.,
The focus of this review is on hippocampal learning and memory, how it changes with age, and the contributions made to age-related cognitive decline by plasticity mechanisms that require protein synthesis. First, studies of overall brain protein synthesis levels are reviewed, and then age-related changes in expression of specific mRNAs and proteins thought to have important roles in plasticity and memory are described. The effects of age-dependent reduced translation on memory and long-lasting forms of synaptic plasticity will be considered, as well as the consequences of altered long-term plasticity on spatial information processing and memory. Lastly, pharmaceutical interventions are discussed that enhance age-related memory loss by modifying signaling pathways that elicit new protein synthesis, and new drug targets for alleviating cognitive aging are suggested based on recently discovered mechanisms of long-lasting synaptic plasticity.
It was not until the 1980s that methods for routinely obtaining accurate measurements of brain proteins became standardized and reliable. Prior to this time, the experimental methods did not consider specific activity of the precursor pool (reviewed by Richardson and Birchenall-Sparks,
Ingvar et al. (
Although it is clear that general protein expression levels in specific brain structures can change during the aging process, more mechanistic insight is derived from examining the expression of individual proteins that are known to have roles in synaptic plasticity and memory. Bishop et al. (
Indeed, the translation of specific proteins is preceded by transcription of the mRNAs that encode these proteins, which can also undergo age-related change. In order to understand the origin of age-related changes in protein expression, research methods have adapted to measure both protein and mRNA synthesis. By combining methodologies such as immunohistochemistry,
The immediate-early genes (IEGs) encode transcription factors that regulate expression of their target genes, and effector proteins that directly influence the state of the cell (reviewed by Sheng and Greenberg,
Of the IEGs that function as transcription factors,
Does
c-Fos is another IEG-encoded protein that can act as a transcription factor (Morgan et al.,
One of the most-studied IEGs in terms of plasticity and memory function is activity-regulated cytoskeleton-associated protein (Arc). Whereas
Hippocampal
Other IEGs that are involved in hippocampal memory and plasticity have potential roles in cognitive aging (e.g., AP-1, Narp, Cox-2, BDNF, tPA, Homer1A, Rheb), but their expression across the lifespan has not yet been examined in enough depth for definitive conclusions (but see Lanahan et al.,
The early work by Flexner and colleagues first demonstrated the importance of protein synthesis in the long-term consolidation of memory. Using puromycin, they were able to show that, for several days after training, new protein synthesis in the temporal lobe is crucial for the later expression of long-term memory (Flexner et al.,
Among the early studies was one conducted by Squire and Barondes (
While there are clearly experimental design issues that arise due to toxicity and potential “non-specific effects” of protein synthesis disruption (Alberini,
Normal aging is often accompanied by memory impairment (for review see Rosenzweig and Barnes,
Barnes and McNaughton (
Oler and Markus (
A further study of contextual fear memory by Ward et al. (
Thus, it appears that in some tasks that depend on an intact hippocampus, the mechanisms required for learning can be largely intact. However, age-related changes in processes necessary for memory stabilization show vulnerability to the aging process.
There are indications that the time course of protein synthesis-dependent memory consolidation might be extended in aged rodents. Davis et al. (
From these data, Essman suggested that memory consolidation processes may be slowed in aged mice as a consequence of cellular/metabolic changes, and/or a slowdown in protein synthesis may impair the consolidation of memory traces. Overall, the authors of these studies interpret these findings to indicate that the transition time from short- to long-term memory is extended during aging, suggesting that a longer time period after training may be required in order for memory consolidation to be successful.
Several more recent studies have examined age-related changes in cAMP responsive element binding protein (CREB) activity as a potential cause of memory impairment in aging. CREB is a transcription factor whose activity is required for hippocampal memory consolidation (Guzowski and McGaugh,
Countryman and Gold (
Mouravlev et al. (
Collectively, there is a large body of evidence for a decline in long-term memory in aged animals, including hippocampal deficits in spatial memory, trace eyeblink conditioning, and contextual fear memory. The intra-hippocampal mechanisms that underlie impaired long-term memory during aging are less clear, but evidence is mounting that irregularities in CREB-dependent transcription are a key contributor in this memory decline. These findings converge with those showing an altered time course of protein synthesis inhibition to suggest that the regulation of protein synthesis differs in aged animals, resulting in a reduced capacity for long-term memory.
Long-term potentiation (LTP) is an activity-dependent enhancement of synaptic transmission (Bliss and Lomo,
Different forms of LTP can be induced by distinct patterns of stimuli; early-LTP (E-LTP) can last minutes to hours and is thought to relate mechanistically to short-term memory, whereas late-LTP (L-LTP) can last hours to days and relies on mechanisms that parallel those of long-term memory (Abraham and Williams,
There is evidence that LTD also participates in hippocampus-dependent memory formation (reviewed by Kemp and Manahan-Vaughan,
Long-term potentiation induction using weak stimulation patterns elicits lower levels of synaptic modification in aged than in young rodents (
However, long-term maintenance of LTP (L-LTP) is impaired in aged rodents, and this often correlates with deficits in hippocampus-dependent memory (
The general decline in LTP maintenance observed in old animals is accompanied with a greater susceptibility to induction of LTD and depotentiation in area CA1 of hippocampal slices (Norris et al.,
Evidence suggests that in advanced age, the activity in some signaling pathways is enhanced, whereas activity in others is diminished. Complex interactions between different patterns of synaptic activity and age-related changes in multiple signaling pathways likely determine the balance between LTP and LTD induction, and maintenance of changes in synaptic strength, in aged animals.
Several definitive molecular changes have been identified in the aged hippocampus that affect synaptic transmission and plasticity. There is a large body of evidence for altered calcium homeostasis in the aged rat hippocampus (e.g., Disterhoft et al.,
The consequences of these age-related changes in calcium handling are far reaching. Calcium action potentials are larger and have increased latency in aged hippocampal neurons (Pitler and Landfield,
NMDAR activity is also reduced in the hippocampus of the aged rat. There are fewer perforant path synapses in the mid-molecular layer of the aged dentate gyrus (Geinisman et al.,
There is some evidence that signaling pathways that can stimulate new transcription and translation undergo changes with aging. The forms of L-LTP that exhibit age-related reductions in maintenance are often induced by multiple, spaced trains of high-frequency activity; these types of induction protocols also elicit activity of the cAMP pathway and CREB in hippocampal neurons (Frey et al.,
Relatively few studies have directly examined molecular mechanisms of reduced L-LTP in aged rodents. Bach et al. (
Although much research has focused on postsynaptic changes following LTP, there is some evidence that new protein synthesis can be initiated in the presynaptic neuron following LTP induction, and that it has a role in regulating the number of synaptic terminals and the rate of vesicle recycling (Malgaroli et al.,
Gooney et al. (
There are indications that the balance between LTP and LTD induction is shifted in aged rodents. Huang and Kandel (
Like Huang and Kandel, Kumar and Foster (
Collectively, the evidence thus far suggests that in the aged rodent, the expression of protein synthesis-dependent synaptic strengthening is diminished, whereas that of protein synthesis-dependent synaptic depression is increased. This may result from changes in calcium homeostasis and signaling pathway activity that affect the balance between induction of synaptic potentiation and depression, and recruitment of protein synthesis processes in the aged.
Although informative, the interpretation of
Many of the basic properties of hippocampal CA1 neuron place fields are intact in aged rats (reviewed by Rosenzweig and Barnes,
Place fields expand when young rats repeatedly traverse the same linear path, and place field centers move slightly “backwards” along the path (Mehta et al.,
This place field expansion plasticity may function to facilitate sequence and path learning (Levy,
Place field expansion is reduced in aged rats such that place fields do not expand to the extent that occurs in young rats through up to 15 traversals of a rectangular track (Shen et al.,
Place field expansion depends on NMDAR activity (Ekstrom et al.,
Place fields form immediately when animals enter an environment for the first time (Bostock et al.,
Interestingly, old rats sometimes express a failure to retrieve previously expressed maps, similar to what occurs when NMDA receptors are blocked during place field encoding. Barnes et al. (
Although place representations in area CA1 are less stable in aged than in young rats when an environment remains consistent (Barnes et al.,
These age differences in CA3 processing may originate with its inputs from granule cells; it is believed that sparse encoding in the dentate gyrus contributes to the coded orthogonalization of spatial information. The dentate gyrus is particularly vulnerable to the effects of aging (Small et al.,
Weakened synaptic plasticity in the aged hippocampus may also result in less binding of landmarks and cues via LTP-like processes to the hippocampal map, as suggested by models in which the map is initially based on self-motion (e.g., McNaughton et al.,
The hippocampus may participate in consolidation of memory to long-term storage sites in the neocortex (e.g., Scoville and Milner,
Because of the hippocampal memory and plasticity impairments seen in aged rats, it was hypothesized that reactivation may be impaired in these animals because it requires long-term persistence of activity patterns within hippocampal networks. Reactivation does occur in the hippocampus of aged rats (Gerrard et al.,
There is considerable evidence that during aging, there are changes in the regulation of protein synthesis. Both transcription and translation are affected; in fact, following artificial or behavioral stimulation, some proteins are expressed to a greater degree in the hippocampi of aged rodents compared to young or adult rodents, and others are expressed less. Similarly, when protein synthesis levels are examined in aged rodents, decreased synthesis is observed in some, but not all, brain regions. These observations converge to show that the whole brain protein synthesis decrease observed in senescence, in fact, represents numerous and complex changes in transcription and translation that can differ from region to region.
Some of these age-related changes in protein synthesis mechanisms have been studied in conjunction with long-term memory. This approach can provide direction for the development of pharmaceutical interventions to alleviate the memory loss that accompanies normal aging. Memantine, for example, is used to treat cognitive impairment and mild to moderate dementia associated with Alzheimer's disease (Rogawski and Wenk,
Another potential avenue for pharmaceutical development is protein kinase M zeta (PKMζ), a molecule that is necessary and sufficient for maintenance of LTP in hippocampal area CA1 (Ling et al.,
It has recently become evident that epigenetic mechanisms may contribute to age-related changes in memory and synaptic plasticity (see review by Penner et al.,
Estrogen treatment has also been examined as a potential memory enhancer especially for the middle aged, as it improves spatial memory, reduces propensity for synaptic depression, and may facilitate hippocampal transcription in female rats (Foster et al.,
Developing a full understanding of changes in transcription and translation during aging will provide deeper insight into which pharmaceutical interventions will be most effective in preventing memory loss. The interactions of many factors in addition to protein synthesis are thought to determine susceptibility to age-related cognitive decline, such as oxidative stress, epigenetic modification of the genome, and age-related changes in neuromodulation and growth factors. Because the composition of neuronal proteins ultimately dictates synaptic function, it might be most effective for future studies to focus on determining how all biological correlates of aging affect the synthesis and activity of proteins known to have roles in long-lasting forms of synaptic plasticity and memory.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supported by the McKnight Brain Research Foundation and AG012609.