Regulation of intrinsic excitability: Roles for learning and memory, aging and Alzheimer's disease, and genetic diversity.

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Neurobiol Learn Mem 2019 Aug 20; 164:107069






AG057914, AG054180, Alzheimer's Association (AARF-18-565506)


Plasticity of intrinsic neuronal excitability facilitates learning and memory across multiple species, with aberrant modulation of this process being linked to the development of neurological symptoms in models of cognitive aging and Alzheimer's disease. Learning-related increases in intrinsic excitability of neurons occurs in a variety of brain regions, and is generally thought to promote information processing and storage through enhancement of synaptic throughput and induction of synaptic plasticity. Experience-dependent changes in intrinsic neuronal excitability rely on activity-dependent gene expression patterns, which can be influenced by genetic and environmental factors, aging, and disease. Reductions in baseline intrinsic excitability, as well as aberrant plasticity of intrinsic neuronal excitability and in some cases pathological hyperexcitability, have been associated with cognitive deficits in animal models of both normal cognitive aging and Alzheimer's disease. Genetic factors that modulate plasticity of intrinsic excitability likely underlie individual differences in cognitive function and susceptibility to cognitive decline. Thus, targeting molecular mediators that either control baseline intrinsic neuronal excitability, subserve learning-related intrinsic neuronal plasticity, and/or promote resilience may be a promising therapeutic strategy for maintaining cognitive function in aging and disease. In this review, we discuss the complementary relationship between intrinsic excitability and learning, with a particular focus on how this relationship varies as a function of age, disease state, and genetic make-up, and how targeting these factors may help to further elucidate our understanding of the role of intrinsic excitability in cognitive function and cognitive decline.


The authors would like to thank Dr. Kristen MS O’Connell for critical review and input to the final manuscript.