Neurological disorders impacting cognition and memory, such as schizophrenia and Alzheimer's disease, afflict millions of Americans. The search for factors involved in neurological disorders has identified disruptions in a fundamental neuronal process, synaptic plasticity, in nearly all pervasive neurological disorders. Synaptic plasticity, widely held to be the cellular substrate of memory, describes the specific modification of neuronal connections in response to experience. Thus, altered mechanisms controlling this process may be causal in the pathophysiology of patients suffering neurological dysfunction. One mechanism thought to play an important part in synaptic plasticity, with an increasingly important role in schizophrenia, intellectual disability and neurodegenerative diseases, is the Akt signaling pathway. Three isoforms of Akt (Akt1/PKB?, Akt2/PkB?, and Akt3/PKB?) are expressed in the brain, and they display some overlapping function but are also known to have distinct physiological roles in organs including the brain. The role played by the different Akt isoforms in synaptic plasticity processes is unknown. This is an important problem to overcome because improved understanding of Akt function in synaptic mechanisms, especially the role of the different isoforms, will allow for improved diagnoses and therapies aimed at treating neurological disorders. Therefore, the main hypothesis driving this proposal is that Akt isoforms are differentially recruited for neuromolecular signaling underlying synaptic plasticity, cognition and memory formation.
The aims of this proposal are to (1) test the hypothesis that Akt isoforms differentially regulate the expression of long-term potentiation (LTP) in the hippocampus, (2) test the hypothesis that Akt isoforms differentially regulate the expression of different forms of long-term depression (LTD) in the hippocampus, (3) test the hypothesis that different Akt isoforms play specific roles in behavior and memory formation. To test these aims, we will use novel pharmacological agents that target pan-Akt and isoform-specific activity, enabling us to modulate Akt function in vivo. To complement this approach, we will also genetically probe the role of Akt in synaptic function, cognition, and memory using Akt mutants. These combined approaches will be applied to electrophysiological, biochemical, and behavioral analyses for examining synaptic plasticity, protein synthesis and behavioral performance in mouse models of neurological disorders. Our approach is conceptually and technically innovative because we will utilize novel pharmacological, genetic, and viral reagents to specifically target Akt isoform function in synaptic processes and behavior. This proposed research is significant because it addresses fundamental questions about the differentiation of neurobiological signaling involved in cognition, which has important implications for mental health. By defining Akt isoform-specific regulation of synaptic plasticity and cognition, our approach will provide new insight into Akt-dependent mechanisms affected in neurological diseases and psychiatric disorders associated with cognitive impairments.

Public Health Relevance

The proposed research is relevant to public health because the identification of cellular mechanisms that promote or increase the severity of human neurological disorders may be used to create new diagnoses for the onset of neurological disease, develop new treatments against diseases, and determine the efficacy of ongoing therapies directed against a disease. As such, the proposed research examining the role of different Akt isoforms in synaptic plasticity, cognition, and memory formation is relevant to the part of the NIH's mission that pertains to developing basic scientific knowledge in the causes, diagnosis, prevention, and cure of human diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Churn, Severn Borden
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University of Colorado at Boulder
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United States
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