Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons

Abstract

Neuromodulatory control by oxytocin is essential to a wide range of social1,2, parental3 and stress-related behaviours4. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels5 and with genetic alterations of the oxytocin receptor (OXTR)6. Thirty years ago, Mühlethaler et al.7 found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron–pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision.

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Figure 1: Oxytocin receptor agonist (TGOT) reduces spontaneous firing but enhances EPSP-spike coupling in CA1 pyramidal neurons.
Figure 2: TGOT activates FSIs and suppresses feed-forward inhibition.
Figure 3: Paired recordings reveal synaptic locus of TGOT-induced decrease in evoked inhibition.
Figure 4: Generalization to other brain states and modulators.

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Acknowledgements

We thank C. Földy for generous assistance with techniques for interneuron recording and classification, and thank Y. Li, M. Tadross, A. Mitra, D. Poburko, L. Prolo, J. Huguenard, S. Hestrin, D. Madison, L. Luo, K. Pelkey and K. Deisseroth for discussion and comments. This work was supported by the Burnett Family Fund, the Mosbacher Fund, and the Mathers Foundation, as well as grants from the National Institute of Mental Health (MH064070, MH071739), the National Institute of Neurological Disorders and Stroke (NS024067) and the Simons Foundation (95395). S.F.O. is supported by an NDSEG fellowship and by an NIMH-NRSA fellowship (F31MH084430). P.L.B. is supported by an SNSF and SFGBM fellowship (PASMP3_140063/1).

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S.F.O. performed all experiments, analysis and modelling. S.N.T. and S.F.O. performed ChR2 experiments. P.L.B. and N.N.T. assisted with interpretation of results and long-term project direction. R.W.T. and G.F. oversaw experiments, analysis, modelling and project direction. S.F.O. and R.W.T. planned and designed experiments and wrote the paper.

Corresponding author

Correspondence to Richard W. Tsien.

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The authors declare no competing financial interests.

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Owen, S., Tuncdemir, S., Bader, P. et al. Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Nature 500, 458–462 (2013). https://doi.org/10.1038/nature12330

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