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

Jelena Borovac; Jayant Rai; Megan Valencia; Hang Li; John Georgiou; Graham L Collingridge; Keizo Takao; Kenichi Okamoto

doi:10.3389/fnmol.2024.1479360

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

Front Mol Neurosci. 2024 Nov 26:17:1479360. doi: 10.3389/fnmol.2024.1479360. eCollection 2024.

Authors

Jelena Borovac^{1

2

3}, Jayant Rai^{1

2}, Megan Valencia^{1

2}, Hang Li¹, John Georgiou¹, Graham L Collingridge^{1

4

5}, Keizo Takao^{3

6

7}, Kenichi Okamoto^{1

2}

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
² Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Department of Behavioral Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
⁴ Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ TANZ Centre for Research in Neurodegenerative Diseases (CRND), University of Toronto, Toronto, ON, Canada.
⁶ Department of Behavioral Physiology, Faculty of Medicine, University of Toyama, Toyama, Japan.
⁷ Research Centre for Idling Brain Science, University of Toyama, Toyama, Japan.

Abstract

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 fiber 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; electrophysiology; long-term potentiation; memory; mouse behaviors; optogenetics; synaptic plasticity.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Canadian Institutes of Health Research (CIHR, MOP111220, PJT 156103, KO), Natural Sciences and Engineering Research Council of Canada Discovery Grants (2017-06444, KO), Canada Foundation for Innovation (KO). This work was supported by the Brain Canada Foundation through the Canada Brain Research Fund, with the financial support of Health Canada. GC is the holder of the Krembil Family Chair in Alzheimer’s Research. JG was supported by Brain Canada and a CIHR Foundation grant to GC. JB was supported by Weston Brain Institute international fellowship in neuroscience. This study was also supported by JSPS KAKENHI (Grant Nos. 16H01270, 16K01946, and 23K17422) to KT.