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Dysregulated GluA2-Y876 phosphorylation contributes to loss of synaptic upscaling in GRIP1 mutant mice with reduced sociability and increased repetitive behavior

Molecular Psychiatry (2025)Cite this article

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Abstract

Loss of synaptic upscaling, a post-synaptic homeostatic plasticity, has been reported in mouse models of autism, but the underlying mechanism remains unknown. Glutamate receptor interacting protein 1 (GRIP1) binds AMPA receptor 2 (GluA2) through its PDZ domains 4-6 where gain-of-function variants were described in autism. We characterized mice carrying one variant, GRIP1-I586L (murine I507L), that shows increased binding with GluA2. Grip1-I507L mice exhibit impaired social interaction and increased repetitive behaviors, increased neuronal excitability and excitatory-to-inhibitory ratio in the medial prefrontal cortex. Grip1-I507L cortical neurons show a loss of synaptic upscaling to tetrodotoxin-induced inactivity. Basal phosphorylation of GluA2-Y876 is increased, which is consistent with increased binding to GluA2 while lack of further induction to inactivity contributes to loss of synaptic upscaling. Phosphorylation of GluA2-S880 that regulates Hebbian plasticity is not altered. These results support that gain-of-function GRIP1 variants are a novel cause of autism-related impaired social interaction and increased repetitive behavior and implicate that dysregulated phosphorylation of GluA2-Y876 is a novel mechanism for loss of synaptic upscaling.

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Fig. 1: Grip1-I507L Results in Increased Binding with GluA2.
Fig. 2: Rodent Behavioral Testing of Grip1-I507L Mice.
Fig. 3: Electrophysiological Characterization of the mPFC Layer 2/3 Pyramidal Neurons and Primary Cultured Neurons from WT and Grip1-I507L Mice.
Fig. 4: Loss of Synaptic Upscaling in Grip1-I507L Cortical Neurons.
Fig. 5: Altered GluA2-Y876 Phosphorylation in Grip1-I507L Cortical Neurons at Basal Condition and in Response to TTX Treatment.

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Data availability

Data supporting the key findings of this study is presented in the article and its supplementary information, and available from the corresponding author upon request. Correspondence and requests for materials should be addressed to twang9@jhmi.edu.

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Acknowledgements

This work was supported in part by Simon Foundation (#206683) and NIMH (RO1 MH112808 to R.H. and T.W.; P50 MH100024 to R.H.; R21 MH128765 to J.K.) and a KBRI basic research program (25-BR-02-02 and 25-BR-07-01) through Korea Brain Research Institute funded by Ministry of Science and ICT to J.K.

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  1. These authors contributed equally: Mei Han, Han L. Tan.

Authors and Affiliations

  1. McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Mei Han, Rebeca Mejías & Tao Wang

  2. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Han L. Tan, Shu-Ling Chiu & Richard L. Huganir

  3. Department of Physiology, University of Seville, 41012, Seville, Spain

    Rebeca Mejías

  4. Instituto de Investigaciones Biomédicas de Sevilla, IBIS/ Universidad de Sevilla/ Hospital Universitario Virgen del Rocío/ Junta de Andalucía/ CSIC, 41013, Seville, Spain

    Rebeca Mejías

  5. Institute of Cellular and Organismic Biology and Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, 11529, Taiwan

    Shu-Ling Chiu

  6. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Juhyun Kim

  7. Emotion, Cognition & Behavior Research Group, Korea Brain Research Institute, Daegu, 41062, Republic of Korea

    Juhyun Kim

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Contributions

M.H., H.L.T., J.K, T.W., and R.L.H. designed research; M.H., H.L.T., R.M., S.-L.C., and J.K. performed research; M.H., H.L.T., J.K. T.W. analyzed data; M.H., H.L.T. J.K., R.L.H. and T.W. wrote the paper.

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Correspondence to Juhyun Kim, Richard L. Huganir or Tao Wang.

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Han, M., Tan, H.L., Mejías, R. et al. Dysregulated GluA2-Y876 phosphorylation contributes to loss of synaptic upscaling in GRIP1 mutant mice with reduced sociability and increased repetitive behavior. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03415-0

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