Linking Insulin Signaling to Age-Related Cognitive Decline : Insulin-Dependent Regulation of Intrinsic Excitability in Aging Hippocampus
Tandon, Neha Ramesh
MetadataShow full item record
The elderly population (age 65 and over) is estimated to double in number by the year 2050. This will increase the socioeconomic burden associated with cognitive decline that accompanies normal aging and pathological aging caused by Alzheimer’s disease (AD) and other dementias. While many pharmacological treatments have shown promise in ameliorating age-related cognitive decline, they have severe side effects. Increase in the amplitude of post-burst afterhyperpolarization (AHP) in aging hippocampal pyramidal neurons decreases its intrinsic excitability and leads to impairment in learning and memory formation of hippocampusdependent tasks. Insulin decreases the amplitude and duration of Ca2+-dependent AHP in aging hippocampus and reveres cognitive deficits. However, the molecular mechanism underlying the insulin-dependent decrease in AHP is as yet unknown. Abundance of insulin receptors in the hippocampus and insulin-sensitivity of pyramidal neurons, makes insulin a potential therapeutic agent to enhance hippocampus-dependent learning and memory in aging. While intracerebroventricular (ICV) or intravenous (IV) application of insulin has shown promising results, these methods are not suitable for clinical trials. Intranasal administration has become a preferred method for delivery of small neuropeptides such as insulin directly to the brain. Dysregulation of insulin signaling in the brain has long been implicated with mild cognitive impairment (MCI), AD and aging brain. Intranasal insulin improved verbal memory in a clinical study with MCI and AD patients. In this dissertation, we utilized chronic (21 days) low dose intranasal insulin application to assess the effects of insulin on hippocampus-dependent spatial and working memory consolidation in aging animals on Morris water maze task. Intranasal insulin significantly enhanced learning and spatial memory in aging rats with cognitive deficits. Next, we sought to study the effect of insulin on proteins involved in Ca2+-dependent intrinsic excitability: (i) the SK2 channel underlying the medium AHP (mAHP), (ii) Ca2+ sensor, calmodulin that gates mAHP, and (iii) Ca2+ sensor, hippocalcin that gates slow AHP (sAHP). Immunoblots using young and aging hippocampus showed (i) downregulation of insulin signaling (ii) over-expression of SK2 (iii) downregulation of calmodulin and (iv) no change in hippocalcin with aging. Ex-vivo insulin stimulation of hippocampal slices was able to (i) restore the insulin signaling in aging, (ii) reverse the age-related overexpression of SK2 and (iii) downregulate the expression of hippocalcin in both young and aging tissue. Our results suggest that manipulation of insulinsignaling in aging can increase hippocampal intrinsic excitability and performance in hippocampus-dependent tasks; and supports the use of intranasal insulin therapy in clinical studies with cognitively impaired aging patients.