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Pten loss results in inappropriate excitatory connectivity

Molecular Psychiatry volume 24, pages 1627–1640 (2019)Cite this article

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Abstract

Pten mutations are associated with autism spectrum disorder. Pten loss of function in neurons increases excitatory synaptic connectivity, contributing to an imbalance between excitation and inhibition. We aimed to determine whether Pten loss results in aberrant connectivity in neural circuits. We compared postnatally generated wild-type and Pten knockout granule neurons integrating into the dentate gyrus using a variety of methods to examine their connectivity. We found that postsynaptic Pten loss provides an advantage to dendritic spines in competition over a limited pool of presynaptic boutons. Retrograde monosynaptic tracing with rabies virus reveals that this results in synaptic contact with more presynaptic partners. Using independently excitable opsins to interrogate multiple inputs onto a single neuron, we found that excess connectivity is established indiscriminately from among glutamatergic afferents. Therefore, Pten loss results in inappropriate connectivity whereby neurons are coupled to a greater number of synaptic partners.

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Acknowledgements

We would like to thank the Dartmouth Autism Research Initiative (DARI; https://sites.dartmouth.edu/autismresearchcenter/) for support.  The work was funded by the National Institute of Mental Health (R01MH097949; to B.W.L.); and by the National Institute of Alcohol Abuse and Alcoholism (R01AA022377), the Whitehall Foundation, and the Hartwell Foundation (to H.S.). Imaging was supported by the optical cellular imaging core at Dartmouth (P30CA023108) and an NIH S10 for the LSM800 (S10OD21616).  We thank Dr. Ed Boyden for the plasmids and viruses containing Chrimson and Chronos, and for his advice on their application (we found that they worked precisely as advertised).

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  1. Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, Hanover, NH, 03755, USA

    Patrick D. Skelton, Paul W. Frazel & Bryan W. Luikart

  2. Department of Neurosciences, Cleveland Clinic, Cleveland, OH, 44195, USA

    Daehoon Lee & Hoonkyo Suh

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Contributions

Conceptualization: P.D.S, H.S., and B.W.L.; Methodology: P.D.S., H.S., and B.W.L.; Investigation: P.D.S., P.W.F., D.L.; Writing—Original Draft: P.D.S.; Writing—Review and Editing: P.D.S., H.S., and B.W.L.; Supervision: H.S. and B.W.L.; Funding Acquisition: H.S. and B.W.L.

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Correspondence to Bryan W. Luikart.

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Skelton, P.D., Frazel, P.W., Lee, D. et al. Pten loss results in inappropriate excitatory connectivity. Mol Psychiatry 24, 1627–1640 (2019). https://doi.org/10.1038/s41380-019-0412-6

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