Synaptic Correlates of Aging and Cognitive Decline

Normal aging is associated with a significant decline in cognitive processes including executive functions and memory. Similar to humans, cognitive decline is highly variable in the aging population of monkeys and rodents and some aged individuals function as well as young adults. Thus identification of neurobiological features that underlie age-related cognitive decline has been the subject of intense investigation. The prefrontal cortex (PFC) has been extensively studied for its critical role in executive function while the hippocampus and related cortical regions have been the major targets of research for memory function. For many years, it was assumed that the decline in cognitive function with aging was a consequence of neuronal loss. However, more recent studies using unbiased stereological techniques have mostly failed to detect age-related neuronal loss in the PFC and hippocampus in the absence of neurodegenerative disease. Due to the lack of anatomical or neuronal number changes with aging, recent effort has focused on investigating the density, morphology, and molecular makeup of synapses and how they relate to aging and cognitive decline. Several of these studies have been carried out in behaviorally characterized young and aged monkeys. Recent evidence suggests that the critical synaptic subtypes associated with cognitive decline are different between the PFC and hippocampus and dependent on the types of cognitive function. In the PFC, the dendritic spine subtype most vulnerable to aging and coupled to task acquisition rate is the smallest of the thin spines. In the hippocampal dentate gyrus, synapse density and size remain stable with aging, but the density of large mushroom spines with perforated synapses correlates with recognition memory accuracy. In addition to these morphological findings, this chapter will also review age-related changes in ionotropic glutamate receptors and how they relate to cognitive function. Finally, the beneficial effects of estrogen on aging and cognitive decline are discussed in the context of potential morphological and molecular mechanisms.