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An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome

Molecular Psychiatry volume 28, pages 1101–1111 (2023)Cite this article

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Abstract

We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.

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Fig. 1: JB2-induced field potential slope increase depends on IGF2R, MAPK/ERK pathway, and transcription and translation.
Fig. 2: JB2 regulates the phosphorylation of postsynaptic autism risk factors in primary cortical cultured rat neurons.
Fig. 3: JB2 rescues synaptic circuit impairments in adult male Shank3+/− mice.
Fig. 4: JB2 rescues behavioral impairments in adult male Shank3+/− mice.
Fig. 5: JB2 produced therapeutic-like effects in Shank3+/− mice using direct mouse-to-human non-invasive translational measures.

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Acknowledgements

This work was supported by R41MH121140 to PP. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. We also thank NU Nikon Cell Imaging Facility. We would also like to thank Joseph Buxbaum for generously providing the Shank3 mice and Paulina Rychenkova for her knowledge and insight into Phelan-McDermid Syndrome.

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Author notes

  1. These authors contributed equally: Jeffrey S. Burgdorf, Sehyoun Yoon.

Authors and Affiliations

  1. Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, 60201, USA

    Jeffrey S. Burgdorf & Joseph R. Moskal

  2. Gate neurosciences, Inc., Carmel, IN, 46032, USA

    Jeffrey S. Burgdorf & Joseph R. Moskal

  3. Department of Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Sehyoun Yoon, Marc Dos Santos, Catherine R. Lammert & Peter Penzes

  4. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Peter Penzes

  5. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Peter Penzes

  6. Northwestern University, Center for Autism and Neurodevelopment, Chicago, IL, 60611, USA

    Peter Penzes

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Contributions

From the Department of Biomedical Engineering (JB, JM) and Neuroscience (SY, MS, CL, PP) Northwestern University, Chicago, Illinois, JB initiated the project and performed MEA recordings in vitro and behavioral tests with EEG/EMG and data analysis. SY performed and analyzed WB, ICC, phosphoproteomic experiments and wrote the paper. MS performed and analyzed IHC. CL advised on MEA analysis. JM advised on behavioral tests. PP supervised the project and interpreted data.

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Correspondence to Peter Penzes.

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JSB is a full-time employee of Gate Neurosciences Inc., (Mount Carmel IN, USA). Northwestern University has the rights to the JB2 with pending patents.

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Burgdorf, J.S., Yoon, S., Dos Santos, M. et al. An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome. Mol Psychiatry 28, 1101–1111 (2023). https://doi.org/10.1038/s41380-022-01904-0

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