Victor Luna, Ph.D.

Investigating synaptic aging and its impact on memory

Abstract

Synapses are the biological basis for all cognition. However, much of our understanding of mammalian synapses are based on studies from young and middle-age animals. Little has been established as to the physiology of synapses in the aged brain. Life experiences and biological hallmarks of aging (e.g., stem cell exhaustion) make the synaptic environment of aged mammals completely different than their younger counterparts. A mechanism that may be maladaptive to young synapses may be adaptive to aged synapses, and vice versa. Our limited understanding of aged synapses has precluded the development of treatments for neuropsychiatric and neurocognitive disorders of aging such as late-life depression and dementia. Our proposed research will begin to fill critical gaps in knowledge by providing fundamental insights into the landmark changes in synaptic composition and physiology that occur during the course of normal aging in outbred laboratory mice. We will be investigating synapses in the dentate gyrus (DG) of the hippocampus since it is one of the most vulnerable brain regions to biological aging and is a center for memory. A unique feature of the DG is that it contains stem cells capable of generating ‘new neurons’ throughout adulthood, a process known as ‘adult hippocampal neurogenesis’ (AHN). AHN promotes ‘memory discrimination’: the ability to distinguish seemingly similar experiences from each other. Much like the rest of the body, the DG is susceptible to stem cell exhaustion—one of the nine biological hallmarks of aging. This results in a drastic decline in AHN to such low levels that many experts have questioned whether AHN is of any importance in aged mice let alone elderly humans. We propose that AHN does in fact significantly support memory discrimination in aged mice and that this is possible because of compensatory synaptic mechanisms that amplify AHN-dependent signals. Specifically, we propose a new model of ‘synaptic scaling’ where the DG compensates for the loss of inputs from new neurons during aging by triggering a ‘scaling up’ of its baseline synaptic excitability in order to maintain activity levels that could support memory discrimination. To execute our studies, we will introduce innovations to the field of aging research that will enable us to determine how DG synapses compensate for stem cell exhaustion and the other hallmarks of biological aging (e.g., mitochondrial dysfunction, loss of proteostasis). Overall, our proposed studies will establish a framework for identifying the distinct set of principles that govern synaptic aging and develop novel approaches for understanding cognitive dysregulation due to disorders of aging.

Reward amount: $150,000

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