Hippocampal‐Specific Insulin Resistance Elicits Synaptic Effects on Glutamate Neurotransmission

Jennifer M. Erichsen; Jennifer L. Woodruff; Claudia A. Grillo; Gerardo G. Piroli; Jim R. Fadel; Lawrence P. Reagan

doi:10.1111/jnc.70083

journal article Open Access Jun 01, 2025

Hippocampal‐Specific Insulin Resistance Elicits Synaptic Effects on Glutamate Neurotransmission

Jennifer M. Erichsen

Jennifer L. Woodruff Claudia A. Grillo Gerardo G. Piroli Jim R. Fadel

Lawrence P. Reagan

Journal of Neurochemistry Vol. 169 No. 6 · Wiley

View at Publisher Save 10.1111/jnc.70083

Abstract

ABSTRACTImpaired insulin signaling in brain regions such as the hippocampus is thought to contribute to the cognitive deficits associated with conditions such as mild cognitive impairment and Alzheimer's disease. We have previously demonstrated a number of adverse effects in rats with hippocampal‐specific insulin resistance, including hippocampal structural defects, impairments in hippocampal‐dependent learning and memory, neuroplasticity deficits, behavioral despair, and anxiety‐like behaviors. Additionally, we showed that hippocampal‐specific insulin resistance decreased the serine phosphorylation of GluA1 and expression of GluN2B. These effects on postsynaptic glutamate receptors were particularly fascinating, due to the proposed theory of the glutamatergic system as a facilitator of hippocampal synaptic transmission. However, the synaptic effects of hippocampal‐specific insulin resistance with regard to glutamate neurotransmission had yet to be elucidated. To address this question, we examined hippocampal glutamate neurochemistry and expression of glutamatergic synaptic proteins in rats with hippocampal‐specific insulin resistance. We also examined the ability of intranasal insulin to impact glutamatergic synapses. We found decreased synaptic concentrations of glutamate in the hippocampus, likely a result of reduced hippocampal vGluT2 expression. Additionally, hippocampal glutamate efflux was significantly increased in rats with hippocampal‐specific insulin resistance in response to a high (12 U), but not a low (0.072 U), dose of intranasal insulin. Our findings indicate that hippocampal‐specific insulin resistance elicits synaptic plasticity deficits in glutamatergic synapses, which may be overcome by intranasal insulin administration.image

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References

Details

Published: Jun 01, 2025
Vol/Issue: 169(6)
License: View

Authors

J

Jennifer M. Erichsen

University of South Carolina School of Medicine Department of Pharmacology, Physiology, and Neuroscience Columbia South Carolina USA

J

Jennifer L. Woodruff

University of South Carolina School of Medicine Department of Pharmacology, Physiology, and Neuroscience Columbia South Carolina USA

C

Claudia A. Grillo

University of South Carolina School of Medicine Department of Pharmacology, Physiology, and Neuroscience Columbia South Carolina USA; Columbia VA Health Care System Columbia South Carolina USA

G

Gerardo G. Piroli

University of South Carolina School of Medicine Department of Pharmacology, Physiology, and Neuroscience Columbia South Carolina USA

J

Jim R. Fadel

University of South Carolina School of Medicine Department of Pharmacology, Physiology, and Neuroscience Columbia South Carolina USA

L

Lawrence P. Reagan

University of South Carolina School of Medicine Department of Pharmacology, Physiology, and Neuroscience Columbia South Carolina USA; Columbia VA Health Care System Columbia South Carolina USA

Funding

National Institutes of Health Award: F31 AG0665401

National Science Foundation Award: IOS‐1656626

Cite This Article

Jennifer M. Erichsen, Jennifer L. Woodruff, Claudia A. Grillo, et al. (2025). Hippocampal‐Specific Insulin Resistance Elicits Synaptic Effects on Glutamate Neurotransmission. Journal of Neurochemistry, 169(6). https://doi.org/10.1111/jnc.70083

Hippocampal‐Specific Insulin Resistance Elicits Synaptic Effects on Glutamate Neurotransmission

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