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Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation

Molecular Psychiatry volume 26, pages 1945–1966 (2021)Cite this article

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Abstract

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan–McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

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Fig. 1: Spontaneous calcium transients in dendritic spines reflect subthreshold synaptic activation.
Fig. 2: Aberrant calcium dynamics in apical dendritic spines in medial prefrontal cortex of R1117X mice.
Fig. 3: Reduced SST interneuron activity in vivo in R1117X mice.
Fig. 4: NMDAR currents in SST interneurons are diminished by the R1117X mutation in Shank3.
Fig. 5: Elevating SST interneuron activity in vivo ameliorates aberrant spine calcium dynamics.
Fig. 6: Behavioral consequences of manipulating prefrontal cortical SST interneurons.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

MATLAB scripts for the present study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank K. Kwan and M. Picciotto for comments on the initial version of this paper; C.S. Chan for advice on electrophysiology; M. Picciotto for supplying pAAV-CMV-dsRed-pSico-GFP; S. Tomita for discussions; and I.-J. Kim for use of microscope. This work was supported by Simons Foundation Autism Research Initiative Pilot Award (ACK). Additional support was provided by National Institute of Mental Health grants R01MH112750 (ACK) and R21MH110712 (ACK), NARSAD Young Investigator Grant (ACK), Alzheimer’s Association Research Fellowship AARF-17-504924 (FA), and James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship (FA).

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  1. Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06511, USA

    Farhan Ali, Ling-Xiao Shao, Danielle M. Gerhard, Katherine Sweasy, Santosh Pothula, Christopher Pittenger, Ronald S. Duman & Alex C. Kwan

  2. Child Study Center, Yale University School of Medicine, New Haven, CT, 06511, USA

    Christopher Pittenger

  3. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06511, USA

    Ronald S. Duman & Alex C. Kwan

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Contributions

FA and ACK designed the research. FA performed surgery, imaging, behavioral experiments, and histology, and analyzed the data. L-XS and FA performed the slice electrophysiology experiments and analyzed the data. DMG, SP, and RSD performed molecular cloning, viral packaging, and in vitro validation. KS assisted with the imaging data analysis. CP assisted with PPI experiments. FA and ACK wrote the paper, with input from all other authors.

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Correspondence to Alex C. Kwan.

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RSD has consulted and/or received research support from Naurex, Lilly, Forest, Johnson & Johnson, Taisho, and Sunovion on unrelated projects. CP has consulted and/or received research support from Biohaven, Blackthorn, Teva, and Brainsway on unrelated projects. The remaining authors declare no competing interests.

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Ali, F., Shao, LX., Gerhard, D.M. et al. Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation. Mol Psychiatry 26, 1945–1966 (2021). https://doi.org/10.1038/s41380-020-0708-6

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