Erichsen Jennifer M, Woodruff Jennifer L, Grillo Claudia A, Piroli Gerardo G, Fadel Jim R, Reagan Lawrence P
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.
J Neurochem. 2025 Jun;169(6):e70083. doi: 10.1111/jnc.70083.
Impaired 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.
海马体等脑区的胰岛素信号受损被认为会导致与轻度认知障碍和阿尔茨海默病等病症相关的认知缺陷。我们之前已经证明，海马体特异性胰岛素抵抗的大鼠存在许多不良影响，包括海马体结构缺陷、海马体依赖性学习和记忆受损、神经可塑性缺陷、行为绝望以及焦虑样行为。此外，我们还表明，海马体特异性胰岛素抵抗会降低GluA1的丝氨酸磷酸化和GluN2B的表达。由于谷氨酸能系统被认为是海马体突触传递的促进者这一理论，这些对突触后谷氨酸受体的影响尤其引人关注。然而，海马体特异性胰岛素抵抗对谷氨酸神经传递的突触效应尚未阐明。为了解决这个问题，我们研究了海马体特异性胰岛素抵抗大鼠的海马体谷氨酸神经化学和谷氨酸能突触蛋白的表达。我们还研究了鼻内胰岛素影响谷氨酸能突触的能力。我们发现海马体中谷氨酸的突触浓度降低，这可能是海马体vGluT2表达减少的结果。此外，海马体特异性胰岛素抵抗的大鼠在接受高剂量（12 U）而非低剂量（0.072 U）鼻内胰岛素后，海马体谷氨酸外流显著增加。我们的研究结果表明，海马体特异性胰岛素抵抗会引发谷氨酸能突触的突触可塑性缺陷，而鼻内胰岛素给药可能会克服这一缺陷。
