Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity
Open accessAbstract
Insulin receptors (IRs) are expressed in discrete neuronal populations in the central nervous system, including the hippocampus. To elucidate the functional role of hippocampal IRs independent of metabolic function, we generated a model of hippocampal-specific insulin resistance using a lentiviral vector expressing an IR antisense sequence (LV-IRAS). LV-IRAS effectively downregulates IR expression in the rat hippocampus without affecting body weight, adiposity, or peripheral glucose homeostasis. Nevertheless, hippocampal neuroplasticity was impaired in LV-IRAS–treated rats. High-frequency stimulation, which evoked robust long-term potentiation (LTP) in brain slices from LV control rats, failed to evoke LTP in LV-IRAS–treated rats. GluN2B subunit levels, as well as the basal level of phosphorylation of GluA1, were reduced in the hippocampus of LV-IRAS rats. Moreover, these deficits in synaptic transmission were associated with impairments in spatial learning. We suggest that alterations in the expression and phosphorylation of glutamate receptor subunits underlie the alterations in LTP and that these changes are responsible for the impairment in hippocampal-dependent learning. Importantly, these learning deficits are strikingly similar to the impairments in complex task performance observed in patients with diabetes, which strengthens the hypothesis that hippocampal insulin resistance is a key mediator of cognitive deficits independent of glycemic control.
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Down-regulation of hippocampal insulin receptor function impairs LTP and spatial memory.
“Down-regulation of hippocampal insulin receptor function impairs LTP and spatial memory.120”
From Intranasal insulin (2021) · cites this paper as [120]
Antisense inactivation of the insulin receptor in hippocampus leads to cognitive impairment without systemic consequences.
“antisense inactivation of the insulin receptor in hippocampus leads to cognitive impairment without systemic consequences”
From Neurobiological and Systemic Effects of Chronic Stress (2017) · cites this paper as [60]
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- Authors
- Grillo, C. A., Piroli, G. G., Lawrence, R. C., Wrighten, S. A., Green, A. J., Wilson, S. P., Sakai, R. R., Kelly, S. J., Wilson, M. A., Mott, D. D., & Reagan, L. P.
- Affiliations
- University of South Carolina (US)
- University of Cincinnati Medical Center (US)
- Corresponding author
- Grillo, Claudia A.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2015-07-27
- Volume
- 64
- Issue
- 11
- Pages
- 3927-3936
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4613975
- OpenAlex
- W2205233891
- Cited by
- 308
- References
- 50
- Citations by year
- 2026: 25 · 2025: 20 · 2024: 28 · 2023: 34 · 2022: 22 · 2021: 31 · 2020: 37 · 2019: 33 · 2018: 35 · 2017: 19 · 2016: 16 · 2015: 6
- FWCI
- 11.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Veterans Affairs (IO1 BX001804)
- National Institutes of Health (NS047728, DK017844)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- insulin receptor, spatial learning, synaptic plasticity, long-term potentiation, GluN2B, GluA1 phosphorylation, glutamate receptor subunits, hippocampal plasticity
- MeSH terms
- Animals, Hippocampus, Insulin Resistance, Male, Neuronal Plasticity, Phosphorylation, Receptor, Insulin, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, Rats, Spatial Learning
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