John H. Morrison

Significance: Aging is often accompanied by cognitive decline. It is of critical importance to understand the synaptic susceptibilities of the glutamatergic neural circuits to age-related cognitive decline and to intervene in this process. Maintenance of synaptic health in the face of aging is a crucially important therapeutic goal. We show that the glutamate modulator, riluzole, prevents age-related memory loss and induces clustering of dendritic spines. Clustering is a critical element of synaptic plasticity that has been previously demonstrated to increase synaptic strength. This study further elucidates neuroplastic changes in the neurocircuits vulnerable to aging and advances therapeutic development to prevent and treat age-related cognitive decline.

Significance: Human and nonhuman primates are vulnerable to age- and menopause-related decline in working memory, a cognitive function reliant on the energy-demanding excitation of prefrontal cortex (PFC) neurons. The number and strength of presynaptic boutons providing inputs to these PFC neurons regulate their excitability. We show that poor working memory in rhesus monkeys is associated with a higher incidence of presynaptic boutons harboring malformed, donut-shaped mitochondria that form abnormally small synaptic contacts. Surgically induced menopause results in working memory impairment and a concomitant increase in presynaptic donut-shaped mitochondria, both of which are reversed by estradiol treatment. Our findings suggest that hormone replacement therapy benefits cognitive aging, in part, by promoting mitochondrial and synaptic health in the PFC.

Preclinical animal models have provided strong evidence that estrogen (E) therapy (ET) enhances cognition and induces spinogenesis in neuronal circuits. However, clinical studies have been inconsistent, with some studies revealing adverse effects of ET, including an increased risk of dementia. In an effort to bridge this disconnect between the preclinical and clinical data, we have developed a nonhuman primate (NHP) model of ET combined with high-resolution dendritic spine analysis of dorsolateral prefrontal cortical (dlPFC) neurons. Previously, we reported cyclic ET in aged, ovariectomized NHPs increased spine density on dlPFC neurons. Here, we report that monkeys treated with cyclic E treatment paired with cyclic progesterone (P), continuous E combined with P (either cyclic or continuous), or unopposed continuous E failed to increase spines on dlPFC neurons. Given that the most prevalent form of ET prescribed to women is a combined and continuous E and P, these data bring into convergence the human neuropsychological findings and preclinical neurobiological evidence that standard hormone therapy in women is unlikely to yield the synaptic benefit presumed to underlie the cognitive enhancement reported in animal models.

Rhesus monkeys provide a valuable model for studying the neurobiological basis of cognitive aging, because they are vulnerable to age-related memory decline in a manner similar to humans. In this study, young and aged monkeys were first tested on a well characterized recognition memory test (delayed nonmatching-to-sample; DNMS). Then, electron microscopic immunocytochemistry was performed to determine the subcellular localization of two proteins in the hippocampal dentate gyrus (DG): the GluA2 subunit of the glutamate AMPA receptor and the atypical protein kinase C ζ isoform (PKMζ). PKMζ promotes memory storage by regulating GluA2-containing AMPA receptor trafficking. Thus, we examined whether the distribution of GluA2 and PKMζ is altered with aging in DG axospinous synapses and whether it is coupled with memory deficits. Monkeys with faster DNMS task acquisition and more accurate recognition memory exhibited higher proportions of dendritic spines coexpressing GluA2 and PKMζ. These double-labeled spines had larger synapses, as measured by postsynaptic density area, than single-labeled and unlabeled spines. Within this population of double-labeled spines, aged monkeys compared with young expressed a lower density of synaptic GluA2 immunogold labeling, which correlated with lower recognition accuracy. Additionally, higher density of synaptic PKMζ labeling in double-labeled spines correlated with both faster task acquisition and better retention. Together, these findings suggest that age-related impairment in maintenance of GluA2 at the synapse in the primate hippocampus is coupled with memory deficits.

Individual differences are a hallmark of cognitive and synaptic ageing. Neurobiological differences between individuals of the same chronological age may underlie the preservation of cognitive abilities in advanced age versus cognitive impairment. In general, age-related cognitive impairments that occur in the absence of neurodegenerative diseases are not associated with loss of cortical neurons. Instead, they seem to be associated with subtle synaptic alterations. The prefrontal cortex controls higher-order, complex behaviours. A hallmark of cognitive ageing is impaired prefrontal function, including impairments in spatial working memory. One synaptic correlate of age-related impairments in working memory that has been identified in monkeys is a loss of thin spines in layer 3 of the dorsolateral prefrontal cortex. The medial temporal lobe, including the hippocampus, is responsible for memories of everyday events. Mild impairments in medial temporal lobe function are also observed in cognitive ageing. A range of synaptic alterations in hippocampal function that correlate with age-related memory impairments have been described. These have been observed in all subfields of the hippocampus and differ between subfields. A notable synaptic alteration in the aged monkey hippocampus is the loss of multisynaptic boutons in the dentate gyrus, which correlates with cognitive impairments. Cyclical oestradiol treatment of aged, surgically menopausal monkeys increases the density of thin dendritic spines in the prefrontal cortex and improves working memory. This illustrates the potential of synaptic and cognitive changes in ageing to be reversible. Loss of synapses may predispose neurons to degeneration in disease states. Thus, a better understanding of mechanisms that promote stability of synapses in ageing should lead not only to amelioration of age-related cognitive impairments but may also affect vulnerability to neurodegenerative diseases.