Cognitive aging is associated with redistribution of synaptic weights in the hippocampus

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others’ lifespans outlast their “mindspans.”

Aging is the biggest risk factor for Alzheimer’s disease, but many aged individuals nevertheless retain the ability to perform cognitive tasks with young adult (YA)-like competency, and are thus resilient to age-related cognitive decline and dementias (1, 2). The mechanisms of such resilience are unknown, but are thought to involve neural or cognitive reserve, brain network adaptations, or simply the ability to maintain cognitive brain circuits in a YA-like state (3–5). Much of the cellular and functional insight into the concept or risk of/resilience against age-related cognitive impairments has come from animal models of normal/nonpathological aging (6–10). Many of these studies have shown that circuit function abnormalities are associated with behavioral impairments. The cellular and structural bases for such functional aberrations, however, remain largely unknown.Two of the most well-studied cognitive domains that show susceptibility to chronological aging in both rodents and nonhuman primates are working memory and spatial/temporal memory (6–10). Importantly, these cognitive domains engage anatomically distinct neurocognitive systems, with the former relying on prefrontal/orbitofrontal cortical circuits and the latter relying on hippocampal circuitry. Interestingly, although behavioral deficits in these two domains (in the case of rat models of cognitive aging) begin to emerge, worsen, and become increasingly prevalent between 12 and 18 mo of age in most strains (reviewed in refs. 9 and 11), cognitive aging within hippocampus-dependent forms of learning and memory are relatively independent of those that engage the prefrontal/orbitofrontal cortical neural systems (6–9, 12–15).Neither the mechanisms underlying the conservation of memory function across chronological aging nor those contributing to the age-related emergence and exacerbation of memory impairments are clearly understood for either neurocognitive system. It is clear, however, that neither frank neuronal loss (16, 17) nor overall synapse loss (18) contributes to cognitive aging within the medial temporal lobe/hippocampal memory system. Rather, the intriguing idea that has emerged from work in both the hippocampal and the prefrontal/orbitofrontal cortical memory systems is that there are functional alterations in the synaptic connections in individual microcircuits embedded within these larger neuroanatomical systems (6–10, 19–31).Axospinous synapses (including those in hippocampal and cortical circuits) are characterized on the basis of the three-dimensional morphology of their postsynaptic densities (PSDs) (20, 32–34). The most-abundant axospinous synaptic subtype has a continuous, macular, disk-shaped PSD, as compared to the less-abundant perforated synaptic subtype, which has at least one discontinuity in its PSD (34). In addition to differing substantially with regard to relative frequency, perforated and nonperforated synapses also harbor major differences in size and synaptic AMPA-type and NMDA-type receptor expression levels (AMPAR and NMDAR, respectively) (34–38). There is also evidence that perforated and nonperforated synapses are differentially involved in synaptic plasticity (39–44) and in preservation of—or reductions in—memory function during chronological aging (6, 20, 45). Layered onto these general distinctions between perforated and nonperforated synapses are more specific differences in their characteristics when considered within neural circuits. For example, perforated synapses have a stronger and more consistent influence on neuronal computation within hippocampal region CA1 than their nonperforated counterparts, which nevertheless outnumber the former by a roughly 9-to-1 ratio (34, 46, 47).These and other circuit-specific differences necessitate a circuit-based approach to understanding the synaptic bases underlying the retention or loss of YA-like memory function in the aging brain. In many ways, the hippocampal system is particularly convenient for such circuit-based approaches (48, 49). Information about the internal and external world is funneled to the parahippocampal system and then relayed via the entorhinal cortex to the dentate gyrus, the first component of the so-called trisynaptic circuit in the hippocampus proper. Granule cells in the dentate gyrus then transmit their computations to hippocampal region CA3 via the mossy fibers, which form very large and anatomically distinct synapses called mossy fiber bouton–thorny excrescence synaptic complexes in the stratum lucidum (SL). CA3 pyramidal neurons then integrate information from their autoassociational connections in the stratum radiatum (SR) and stratum oriens (SO), with both direct entorhinal inputs in stratum lacunosum-moleculare (SLM) and the dentate gyrus inputs in the SL, and convey this information to hippocampal CA1 pyramidal neurons. Neurons in hippocampal CA1 then integrate this information in their basal and apical SR dendrites with direct entorhinal cortical inputs in their most distal, tufted dendrites in the SLM, and represent the first and largest extrahippocampal output from the hippocampus proper. Thus, the computations performed both within individual hippocampal subregions and between them as an interconnected neurocognitive system are complex, and involve a combination of intrinsic (i.e., membrane-bound ion channels that regulate membrane excitability) and synaptic (i.e., ligand-gated ion channels expressed at both excitatory and inhibitory synapses) influences. Additionally, age-related changes at any level of these complex circuits will have downstream consequences on the accuracy/reliability of the information being relayed to extrahippocampal regions via CA1 pyramidal neurons.Given the amount of evidence supporting a possible synaptic explanation for age-related learning and memory impairments in hippocampus-dependent forms of cognition (6–10), we combined patch-clamp physiology, serial section conventional and immunogold electron microscopy (EM), quantitative Western blot analyses, and behavioral characterization using two hippocampus-dependent forms of learning in YA (6- to 8-mo old) and aged rats (28- to 29-mo old) to examine two interconnected hippocampal regions implicated in cognitive aging: Regions CA1 and CA3. We focused on CA1 and CA3 because of their central location in the hippocampal circuit (48–50), their similar laminar dendritic structure (48–50), and their well-documented age-related changes in place field specificity and reliability (51–56).We find that the synaptic architecture and balance of synaptic weights in YA and aged, learning-unimpaired (AU) rats is remarkably similar, but that both are different in aged, learning-impaired (AI) rats. Moreover, this restructuring among “unsuccessful” cognitive agers has an intriguing specificity: It involves only AMPARs, only perforated axospinous synapses, and only hippocampal region CA3, which together shift the balance of synaptic weights that drive action potential output in CA3 pyramidal neurons maladaptively toward an overemphasis of the autoassociational synapses that interconnect CA3 pyramidal neurons.