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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Neuroplasticity and Development
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1479360
This article is part of the Research Topic Spatio-temporal Molecular Mechanisms Regulating Synapse Function and Neural Circuit Dynamics View all 7 articles

Optogenetic elevation of postsynaptic cGMP in the hippocampal dentate gyrus enhances LTP and modifies mouse behaviors

Provisionally accepted
Jelena Borovac Jelena Borovac 1Jayant Rai Jayant Rai 2Megan Valencia Megan Valencia 1Hang Li Hang Li 3John Georgiou John Georgiou 3Graham L. Collingridge Graham L. Collingridge 4Keizo Takao Keizo Takao 5*Kenichi Okamoto Kenichi Okamoto 6*
  • 1 Department of Molecular Genetics, Temerty Faculty of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  • 2 Dearment of Molecular Genetics, Temerty Faculty of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  • 3 Lunenfeld-Tanembaum Research Insitute, Mount Sinai Hospital, Toronto, Canada
  • 4 Dearment of physiology, Temerty Faculty of Medicine, TANZ Centre for Research in Neurodegenerative Diseases (CRND), Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  • 5 Department of Behavioral Physiology, Graduate School of Medicine and Pharmaceutical Sciences, Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Japan
  • 6 Department of Molecular Gentetics, Temerty Faculty of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

The final, formatted version of the article will be published soon.

    A major intracellular messenger implicated in synaptic plasticity and cognitive functions both in health and disease is cyclic GMP (cGMP). Utilizing a photoactivatable guanylyl cyclase (BlgC) actuator to increase cGMP in dentate granule neurons of the hippocampus by light, we studied the effects of spatiotemporal cGMP elevations in synaptic and cognitive functions. At medial perforant path to dentate gyrus (MPP-DG) synapses, we found enhanced long-term potentiation (LTP) of synaptic responses when postsynaptic cGMP was elevated during the induction period. Basal synaptic transmission and the paired pulse ratio were unaffected, suggesting the cGMP effect on LTP was postsynaptic in origin. In behaving mice implanted with a fibre optic and wireless LED device, their performance following DG photoactivation (5 -10 min) was studied in a variety of behavioral tasks. There were enhancements in reference memory and social behavior within tens of minutes following DG BlgC photoactivation, and with time (hours) an anxiogenic effect developed. Thus, postsynaptic cGMP elevations specifically in the DG and specifically during conditions that evoke synaptic plasticity or during experience, are able to rapidly modify synaptic strength and behavioral responses, respectively. The optogenetics technology and new roles for cGMP in the DG may have applications in brain disorders that are impacted by dysregulated cGMP signaling, such as Alzheimer's disease.

    Keywords: cGMP, optogenetics, Electrophysiology, Long-Term Potentiation, synaptic plasticity, Memory, Mouse behaviors

    Received: 12 Aug 2024; Accepted: 18 Oct 2024.

    Copyright: © 2024 Borovac, Rai, Valencia, Li, Georgiou, Collingridge, Takao and Okamoto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Keizo Takao, Department of Behavioral Physiology, Graduate School of Medicine and Pharmaceutical Sciences, Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Japan
    Kenichi Okamoto, Department of Molecular Gentetics, Temerty Faculty of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, M5G 1X5, Ontario, Canada

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