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Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network

Nature Neuroscience 20, 219–229 (2017) | Download Citation

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Abstract

Hippocampal network activity is generated by a complex interplay between excitatory pyramidal cells and inhibitory interneurons. Although much is known about the molecular properties of excitatory synapses on pyramidal cells, comparatively little is known about excitatory synapses on interneurons. Here we show that conditional deletion of the postsynaptic cell adhesion molecule neuroligin-3 in parvalbumin interneurons causes a decrease in NMDA-receptor-mediated postsynaptic currents and an increase in presynaptic glutamate release probability by selectively impairing the inhibition of glutamate release by presynaptic Group III metabotropic glutamate receptors. As a result, the neuroligin-3 deletion altered network activity by reducing gamma oscillations and sharp wave ripples, changes associated with a decrease in extinction of contextual fear memories. These results demonstrate that neuroligin-3 specifies the properties of excitatory synapses on parvalbumin-containing interneurons by a retrograde trans-synaptic mechanism and suggest a molecular pathway whereby neuroligin-3 mutations contribute to neuropsychiatric disorders.

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Acknowledgements

We thank S. Maxeiner for sharing NL3fl mice, S. Fang and S. Atiyeh Afjei for help with stereotaxic injections, K. Lee for help with in vivo recording experiments and S. Botelho for help with biochemical assays. This work was supported by grants from NIH (P50MH086403 to R.C.M. and T.C.S.) and the Simons Foundation Autism Research Initiative Award 307762 (to T.C.S.).

Author information

Affiliations

  1. Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA.

    • Jai S Polepalli
    • , Debanjan Goswami
    •  & Robert C Malenka

  2. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.

    • Hemmings Wu
    •  & Casey H Halpern

  3. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.

    • Thomas C Südhof

  4. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.

    • Thomas C Südhof

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Contributions

J.S.P., T.C.S. and R.C.M. conceived the project, designed the experiments, and wrote and edited the manuscript. H.W. performed the in vivo electrophysiology experiments with input from C.H.H., and D.G. performed the immunohistochemistry experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Robert C Malenka.

Integrated supplementary information

Supplementary figures

  1. 1.

    Generation of NL3fl/PV-Cre mice and quantification of PV interneuron distribution in the hippocampus

  2. 2.

    AAV injection at P21

  3. 3.

    Inhibitory synaptic transmission onto PV interneurons is not changed by NL3 deletion.

  4. 4.

    Summary plots of raw data showing the effects of various drugs on EPSCs and PPRs in PV interneurons.

  5. 5.

    GABAB-receptor- and A1-receptor-mediated presynaptic inhibition of excitatory synaptic transmission in PV interneurons are not affected by NL3 deletion

  6. 6.

    Frequency-dependent attenuation of EPSCs in PV interneurons in PV-Cre and NL3fl/PV-Cre mice.

  7. 7.

    In vivo hippocampal CA1 LFPs show differences between PV-Cre and NL3fl/PV-Cre mice

  8. 8.

    Virally injected DIO-NL3-Venus infects the majority of PV cells in the hippocampus.

  9. 9.

    Rescue of synaptic changes in NL3fl/PV-Cre cells by selective re-expression of NL3.

  10. 10.

    Performance in a reward alternation task and locomotor activity are not affected by deletion of NL3 from PV cells.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–10

  2. 2.

    Supplementary Methods Checklist

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DOI

https://doi.org/10.1038/nn.4471

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