Astrocytic IGF-IRs induce adenosine-mediated inhibitory downregulation and improve sensory discrimination

José Antonio Noriega-Prieto, Laura Eva Maglio, Jonathan A. Zegarra-Valdivia, Jaime Pignatelli, Ana M. Fernandez, Laura Martinez-Rachadell, Jansen Fernandes, Ángel Núñez, Alfonso Araque, Ignacio Torres-Alemán, David Fernández de Sevilla

Research output: Contribution to journalArticlepeer-review

Abstract

Insulin-like growth factor-I (IGF-I) signaling plays a key role in learning and memory processes. While the effects of IGF-I on neurons have been studied extensively, the involvement of astrocytes in IGF-I signaling and the consequences on synaptic plasticity and animal behavior remain unknown. We have found that IGF-I induces long-term potentiation (LTP IGFI) of the postsynaptic potentials that is caused by a long-term depression of inhibitory synaptic transmission in mice. We have demonstrated that this long-lasting decrease in the inhibitory synaptic transmission is evoked by astrocytic activation through its IGF-I receptors (IGF-IRs). We show that LTP IGFI not only increases the output of pyramidal neurons, but also favors the NMDAR-dependent LTP, resulting in the crucial information processing at the barrel cortex since specific deletion of IGF-IR in cortical astrocytes impairs the whisker discrimination task. Our work reveals a novel mechanism and functional consequences of IGF-I signaling on cortical inhibitory synaptic plasticity and animal behavior, revealing that astrocytes are key elements in these processes. SIGNIFICANCE STATEMENT Insulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that astrocytes respond to IGF-I signaling, elevating their intracellular Ca 2+ and stimulating the release of ATP/adenosine, which triggers the LTD of cortical inhibitory synapses, thus regulating the behavioral task performance related to cortical sensory information processing. Therefore, the present work represents a major conceptual advance in our knowledge of the cellular basis of IGF-I signaling in brain function, by including for the first time astrocytes as key mediators of IGF-I actions on synaptic plasticity, cortical sensory information discrimination and animal behavior.

Original languageEnglish (US)
Pages (from-to)4768-4781
Number of pages14
JournalJournal of Neuroscience
Volume41
Issue number22
DOIs
StatePublished - Jun 2 2021

Bibliographical note

Funding Information:
through the National Fund for Scientific and Technological Development (FONDECYT, Perú). J.F. received a postdoctoral fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; Grants #2017/ 14742-0 and #2019/03368-5). We thank the University of Minnesota Viral Vector and Cloning Core for production of some of the viral vectors used in this study; and Dr. G. Perea and Dr. Washington Buño for helpful comments. *J.A.N.-P. and L.E.M. contributed equally to this research. The authors declare no competing financial interests. Correspondence should be a addressed to David Fernández de Sevilla at david.fernandezdesevilla@uam.es. https://doi.org/10.1523/JNEUROSCI.0005-21.2021 Copyright © 2021 the authors

Funding Information:
This work was supported by Grants BFU2016-80802-P from Agencia Estatal de Investigaci?n Spain/Fondo Europeo de Desarrollo Regional, and from the European Union [Ministerio de Econom?a y Competitividad (MINECO)] to D.F.d.S.; Grants R01-NS-097312 and R01-DA-048822 from National Institutes of Health/National Institute of Neurological Disorders and Stroke to A.A.; and grants from Centro de Investigaci?n Biom?dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Grant SAF2016-76462-C2-1-P from MINECO to I.T.-A. J.A.Z.-V. was supported by the National Council of Science, Technology and Technological Innovation (CONCYTEC, Per?) through the National Fund for Scientific and Technological Development (FONDECYT, Per?). J.F. received a postdoctoral fellowship from Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (FAPESP; Grants #2017/ 14742-0 and #2019/03368-5). We thank the University of Minnesota Viral Vector and Cloning Core for production of some of the viral vectors used in this study; and Dr. G. Perea and Dr. Washington Bu?o for helpful comments.

Funding Information:
This work was supported by Grants BFU2016-80802-P from Agencia Estatal de Investigación Spain/Fondo Europeo de Desarrollo Regional, and from the European Union [Ministerio de Economía y Competitividad (MINECO)] to D.F.d.S.; Grants R01-NS-097312 and R01-DA-048822 from National Institutes of Health/National Institute of Neurological Disorders and Stroke to A.A.; and grants from Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Grant SAF2016-76462-C2-1-P from MINECO to I.T.-A. J.A.Z.-V. was supported by the National Council of Science, Technology and Technological Innovation (CONCYTEC, Perú)

Publisher Copyright:
Copyright © 2021 the authors

Keywords

  • Astrocytes
  • Barrel cortex
  • IGF-I
  • Long-term depression
  • Long-term potentiation
  • Sensory discrimination

PubMed: MeSH publication types

  • Journal Article

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