Abstract
The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline.
Highlights
Age-related cognitive impairments are observed across multiple species, including laboratory rodents and humans
Three sections from each animal were stained for NeuN and GFP, to determine the percentage of neurons that were GFP-positive (GFP+): i.e., cells that had been infected by associated viral vector (AAV)-cAMP response element-binding protein (CREB) virus
One sample t-tests against a hypothetical average of 100% revealed that GFP+ cells expressed more CREB than GFP- cells in both young (151.4 ± 5.16%, t4 = 9.97, p=0.0006) and aged (141.0 ± 3.44%, t3 = 11.91, p=0.0013) animals, and no differences were observed in CREB expression of GFP+ cells between young and aged animals (t7 = 1.59, n.s.; Figure 1d)
Summary
Age-related cognitive impairments are observed across multiple species, including laboratory rodents and humans. Age-related cognitive deficits have been observed across numerous tasks and species, not all aged subjects display these impairments (Gallagher and Pelleymounter, 1988; Knuttinen et al, 2001a, 2001b). The aging population can be split into aged individuals who are cognitively-impaired, and others who are cognitively-unimpaired These cognitively-unimpaired ‘super agers’ are capable of learning and remembering at young-like levels (Curlik et al, 2014; Gallagher and Pelleymounter, 1988; Knuttinen et al, 2001a; Rogalski et al, 2013). One likely mechanism contributing to age-related cognitive deficits is a decrease in the intrinsic excitability of CA1 pyramidal neurons.
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