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bioRxiv · 10.1101/2023.12.29.573627

Bidirectional Modulation Of Synaptic Transmission By Insulin-Like Growth Factor I

Noriega-Prieto, J. A.·Maglio, L. E.·Davila, J. C.·Gutierrez, A.·Torres Aleman, I.·Fernandez de Sevilla, D.
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Abstract

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity, and is an essential factor in learning and memory processes. Indeed, we have demonstrated that IGF-IR activation induces long-term potentiation (LTP) of synaptic transmission (LTPIGF-I) both in the barrel cortex, improving object recognition (Noriega-Prieto et al., 2021), and in the prefrontal cortex, facilitating the extinction of conditioned fear (Maglio et al., 2021). However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of NMDAR-dependent LTP at layer 2/3 PNs of the mouse barrel cortex is favored or prevented by IGF-I (10nM) or IGF-I (7nM), respectively, when IGF-I is applied 1 hour before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing LTD of the inhibitory post-synaptic currents (IPSCs), 7nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain. SIGNIFICANCE STATEMENTInsulin-like growth factor-I (IGF-I) signalling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory, and brain pathology, such as Alzheimer disease. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that IGF-I signalling triggers long-term potentiation (LTP) or long-term depression (LTD) of synaptic transmission at cortical synapses in a concentration dependent manner, thus regulating the induction of Hebbian synaptic plasticity. The present work represents an important conceptual advance in our knowledge of the cellular basis of IGF-I signalling in brain function.

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Noriega-Prieto, J. A., Maglio, L. E., Davila, J. C., Gutierrez, A., Torres Aleman, I., Fernandez de Sevilla, D.. 2023-12-29. Bidirectional Modulation Of Synaptic Transmission By Insulin-Like Growth Factor I. https://doi.org/10.1101/2023.12.29.573627

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