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Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility

Molecular Psychiatry volume 27, pages 3272–3285 (2022)Cite this article

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Abstract

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and found that these mice have deficits in fear conditioning memory recall and spatial memory, as well as reduced cortical neuron dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute specifically to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.

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Fig. 1: Cognitive deficits observed in GIT1-NKO mice tested in a battery of behavioral paradigms.
Fig. 2: Global functional and synaptic analyses of mouse hippocampal proteome and phospho-proteome.
Fig. 3: Enrichment of synaptic proteins in the set of hippocampal phospho-proteins regulated by GIT1.
Fig. 4: GIT1-regulated synaptic phosphorylation signaling events within a network of neuropsychiatric risk genes.

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Acknowledgements

We thank members of the Stanley Center for Psychiatric Research and the Chemical Neurobiology Laboratory for helpful discussions and critical feedback. Dr. Guoping Feng is thanked for generously sharing GIT1 mice and for his critical feedback. This work was supported by funding from the Stanley Medical Research Institute, the National Institute of Mental Health (R01MH095088), and the Stuart & Suzanne Steele MGH Research Scholar Award (SJH).

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Author notes

  1. Michael C. Lewis

    Present address: Sage Therapeutics, Cambridge, MA, USA

  2. Rushdy Ahmad

    Present address: Wyss Institute at Harvard University, Boston, MA, USA

  3. Matthew J. Szucs

    Present address: Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, USA

  4. Myung Jong Kim

    Present address: Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

  5. Jonathan Biag

    Present address: Novartis Pharmaceuticals, Cambridge, MA, USA

  6. These authors contributed equally: Daniel M. Fass, Michael C. Lewis, Rushdy Ahmad.

Authors and Affiliations

  1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, 02142, USA

    Daniel M. Fass, Michael C. Lewis, Morgan Fleishman, Myung Jong Kim, Jonathan Biag, Edward M. Scolnick & Stephen J. Haggarty

  2. Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    Daniel M. Fass & Stephen J. Haggarty

  3. Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA, 02142, USA

    Rushdy Ahmad, Matthew J. Szucs, Steven A. Carr & Edward M. Scolnick

  4. McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Qiangge Zhang, Morgan Fleishman & Dongqing Wang

  5. Harrington Discovery Institute, Cleveland, OH, 44106, USA

    Richard T. Premont

  6. Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA

    Richard T. Premont

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Contributions

SJH, EMS, DMF, MCL, RA, MJK, RTP, and SAC designed the study. DMF, MCL, MJS, QZ, MF, DW, JB, RTP, and SJH conducted the experiments and analyzed data. DMF and SJH wrote the manuscript, and all authors edited the manuscript.

Corresponding author

Correspondence to Stephen J. Haggarty.

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Competing interests

SJH is a member of the SAB and equity holder of Psy Therapeutics, Frequency Therapeutics, Sensorium Therapeutics, 4 M Therapeutics, and Proximity Therapeutics; and has received speaking/consulting fees from AstraZeneca, Amgen, Merck, and Syros, and RBNC. DMF has received consulting fees from Psy Therapeutics. None of these entities were involved in the current study.

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Fass, D.M., Lewis, M.C., Ahmad, R. et al. Brain-specific deletion of GIT1 impairs cognition and alters phosphorylation of synaptic protein networks implicated in schizophrenia susceptibility. Mol Psychiatry 27, 3272–3285 (2022). https://doi.org/10.1038/s41380-022-01557-z

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  • DOI: https://doi.org/10.1038/s41380-022-01557-z

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