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Optogenetic inhibition of long-term potentiation in the mouse dentate gyrus

An Schreurs1, Nele Leenders1, Victor Sabanov1, Chris Van Den Haute2, Marleen Welkenhuysen3, Luis Hoffman3, Dries Braeken3, Veerle Baekelandt2 and Detlef Balschun1*
  • 1 KU Leuven, Faculty of Psychology and Educational Sciences, Brain & Cognition, Laboratory of Biological Psychology, Belgium
  • 2 KU Leuven, Department of Neurosciences, Neurobiology and Gene Therapy, Belgium
  • 3 imec, Life Science Technologies Department, Belgium

The hippocampus has a major role in learning and episodic, spatial and emotional memory. Its main information input comes from the entorhinal cortex and enters the dentate gyrus (DG), from where it is processed along the so-called trisynaptic circuit. DG granule cells play a crucial role in pattern separation – the distinction between new and old, previously-stored information. Two main neurobiological phenomena underlie this function: synaptic plasticity (McHugh et al., 2007), the experience-dependent modification of synaptic transmission efficiency, and adult hippocampal neurogenesis (Sahay et al., 2011), the development of adult-born granule cells. Both mechanisms interact, as adult-born neurons show higher levels of synaptic plasticity during maturation, which in turn seems to facilitate pattern separation (Kheirbek et al., 2012). In addition, we recently found marked differences in long-term potentiation (LTP), the best-studied form of synaptic plasticity, at perforant path-granule cell synapses along the hippocampal dorsoventral axis (Schreurs et al., in revision). This adds a further decisive variable of DG information processing. A state-of-the-art tool in the neuroscience field is optogenetics, a genetic engineering method that allows activation or inhibition of specific neuronal (sub)populations by light. In this preliminary study, we aimed to optimize the method for use in the mouse DG in combination with in vitro electrophysiology. Briefly, we stereotactically injected either the CaMKIIa-GtACR2-mCherry adeno-associated viral (AAV) vector construct or the same volume of saline in the dorsal DG of 6 weeks-old mice. We later prepared acute hippocampal slices and assessed the vector expression using a fluorescence microscope. Next, we investigated whether LTP could be induced by high-frequency stimulation (HFS) when the cells were simultaneously illuminated with blue light, to activate the inhibiting GtACR2 opsin (Govorunova et al., 2015). Hereto we employed the recently developed ‘multi-electrode-optrode array’ (Welkenhuysen et al., 2016). We find that in vector- but not saline-injected animals, a single 1s pulse of blue light is sufficient to cause a dramatic reduction in LTP. Intriguingly, a second HFS train one hour later also failed to induce LTP, suggesting long-lasting effects of the optogenetic manipulation. We are currently performing additional control experiments using a CaMKIIa-mCherry control vector, together with immunohistochemistry to confirm correct injection location and to assess the transduction spread in more detail.

Acknowledgements

This work was funded by the Agency for Innovation by Science and Technology (IWT) in Flanders (SBO project 110068 ‘Optobrain’ and doctoral scholarship 141698 to AS).

References

Govorunova, E. G., Sineshchekov, O. A., Janz, R., Liu, X., and Spudich, J. L. (2015). Natural light-gated anion channels: A family of microbial rhodopsins for advanced optogenetics. Science 349, 647–650. doi:10.1126/science.aaa7484.

Kheirbek, M. A., Tannenholz, L., and Hen, R. (2012). NR2B-Dependent Plasticity of Adult-Born Granule Cells is Necessary for Context Discrimination. J. Neurosci. 32, 8696–8702. doi:10.1523/JNEUROSCI.1692-12.2012.

McHugh, T. J., Jones, M. W., Quinn, J. J., Balthasar, N., Coppari, R., Elmquist, J. K., et al. (2007). Dentate Gyrus NMDA Receptors Mediate Rapid Pattern Separation in the Hippocampal Network. Science 317, 94–99. doi:10.1126/science.1140263.

Sahay, A., Scobie, K. N., Hill, A. S., O’Carroll, C. M., Kheirbek, M. a, Burghardt, N. S., et al. (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–70. doi:10.1038/nature09817.

Schreurs, A., Sabanov, V., and Balschun, D. (in revision). Distinct Properties of Long-Term Potentiation in the Dentate Gyrus along the Dorsoventral Axis: Influence of Age and Inhibition. Sci. Rep.

Welkenhuysen, M., Hoffman, L., Luo, Z., De Proft, A., Van den Haute, C., Baekelandt, V., et al. (2016). An integrated multi-electrode-optrode array for in vitro optogenetics. Sci. Rep. 6, 20353. doi:10.1038/srep20353.

Keywords: Hippocampus, Dentate Gyrus, synaptic plasticity, optogenetics, GtACR2 opsin, in vitro electrophysiology, multi-electrode-optrode array

Conference: 12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017.

Presentation Type: Oral Presentation

Topic: Neural Excitability, Synapses, and Glia: Cellular Mechanisms

Citation: Schreurs A, Leenders N, Sabanov V, Van Den Haute C, Welkenhuysen M, Hoffman L, Braeken D, Baekelandt V and Balschun D (2019). Optogenetic inhibition of long-term potentiation in the mouse dentate gyrus. Front. Neurosci. Conference Abstract: 12th National Congress of the Belgian Society for Neuroscience. doi: 10.3389/conf.fnins.2017.94.00047

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Received: 24 Apr 2017; Published Online: 25 Jan 2019.

* Correspondence: Mr. Detlef Balschun, KU Leuven, Faculty of Psychology and Educational Sciences, Brain & Cognition, Laboratory of Biological Psychology, Leuven, 3000, Belgium, detlef.balschun@ppw.kuleuven.be