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Midbrain dopamine neurons bidirectionally regulate CA3-CA1 synaptic drive

Nature Neuroscience volume 18, pages 1763–1771 (2015)Cite this article

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Abstract

Dopamine (DA) is required for hippocampal-dependent memory and long-term potentiation (LTP) at CA1 Schaffer collateral (SC) synapses. It is therefore surprising that exogenously applied DA has little effect on SC synapses, but suppresses CA1 perforant path (PP) inputs. To examine DA actions under more physiological conditions, we used optogenetics to release DA from ventral tegmental area inputs to hippocampus. Unlike exogenous DA application, optogenetic release of DA caused a bidirectional, activity-dependent modulation of SC synapses, with no effect on PP inputs. Low levels of DA release, simulating tonic DA neuron firing, depressed the SC response through a D4 receptor–dependent enhancement of feedforward inhibition mediated by parvalbumin-expressing interneurons. Higher levels of DA release, simulating phasic firing, increased SC responses through a D1 receptor–dependent enhancement of excitatory transmission. Thus, tonic-phasic transitions in DA neuron firing in response to motivational demands may cause a modulatory switch from inhibition to enhancement of hippocampal information flow.

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Figure 1: DA bath application and VTA/SNpC axon stimulation suppress distinct input pathways to CA1.
Figure 2: DA release from VTA/SNpC fibers suppresses SC-evoked depolarization of CA1 PNs by activating D4 receptors.
Figure 3: VTA and SNpC photostimulation suppresses the SC-evoked depolarization of CA1 PNs by enhancing FFI.
Figure 4: PV+ INs mediate the effect of DA release from VTA and SNpC inputs to inhibit the SC-evoked PSP.
Figure 5: Photostimulation of VTA and SNpC afferents enhances the SC-evoked EPSP in PV+ INs.
Figure 6: Repeated photostimulation of VTA and SNpC afferents enhances the SC-evoked PSP in CA1 PNs by activating D1-type receptors.
Figure 7: Pharmacological sensitivity of the effect of DA release on the SC-evoked PSP using 25 bursts of photostimulation.
Figure 8: Fictive tonic and phasic optogenetic stimulation suppresses and enhances the SC-evoked PSP, respectively.

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Acknowledgements

We thank J. Basu (New York University) for her theoretical and technical support with experiments and for helpful comments on the manuscript. We are grateful to S. Sternson for providing the PSEM compound and PSAM construct (Janelia Research Campus, Howard Hughes Medical Institute). The work was supported by funding from the Howard Hughes Medical Institute and a grant from the US National Institutes of Health (5T32MH015174).

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Authors and Affiliations

  1. Department of Neuroscience, Columbia University, New York, New York, USA

    Zev B Rosen, Stephanie Cheung & Steven A Siegelbaum

  2. Department of Pharmacology, Columbia University, New York, New York, USA

    Steven A Siegelbaum

  3. Kavli Institute for Brain Science, Columbia University, New York, New York, USA

    Steven A Siegelbaum

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Contributions

Z.B.R. conducted the electrophysiological experiments. Z.B.R. and S.C. performed the immunohistochemistry. Z.B.R. and S.A.S. designed the experiments and wrote the manuscript.

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Correspondence to Steven A Siegelbaum.

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Integrated supplementary information

Supplementary Figure 1 DA release does not induce rapid changes in intrinsic membrane properties

(a) Schematic of the light burst, which consisted of 3 pulses (5 ms each) with a 10 ms interpulse interval (66.7 Hz). (b) Input resistance before and after photostimulation. Pre = five minutes prior to the light burst protocol. Post = 15 minutes following a single light burst. (c) Input resistance before and after 20 ΩM DA bath application.

Supplementary Figure 2 IPSCs evoked by direct stimulation of GABAergic interneurons throughout CA1 are unaffected by DA release.

(a) Effects of DA release on direct inhibition of CA1 PNs as measured by the IPSC recorded under whole cell voltage clamp at + 10 mV in the presence of NBQX and D-APV. (b) Comparison of the population mean direct IPSCs recorded from CA1 PNs in response to electrical stimulation using an electrode placed in the indicated four layers of CA1, plus the feedforward IPSC evoked by SC stimulation with excitation intact. For direct inhibition experiments, NBQX and D-AP5 were included in the bath solution. Photostimulation of DA release caused no statistically significant change in the direct IPSCs evoked with stimulating electrode in SO. In contrast DA release significantly increased the feedforward IPSC (P values?). (c) Current recording in CA1 pyramidal neurons at a holding potential of +10 mV. Photostimulation protocol is equivalent to the one used in the previous current clamp experiments and shown to scale.

Supplementary Figure 3 Prolonged optogenetic stimulation has no effect on feedforward IPSC.

(a) Experimental configuration. (b) Effect of prolonged optogenetic stimulation on the SC-evoked IPSC measured in voltage clamp at +10 mV as in Figure 3. Closed blue circles: effect of single burst stimulation on the mean IPSC peak amplitude normalized to the baseline. Closed black circles: effect of prolonged burst stimulation.

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Rosen, Z., Cheung, S. & Siegelbaum, S. Midbrain dopamine neurons bidirectionally regulate CA3-CA1 synaptic drive. Nat Neurosci 18, 1763–1771 (2015). https://doi.org/10.1038/nn.4152

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