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Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model

Neuropsychopharmacology volumeĀ 50,Ā pages 772ā€“782 (2025)Cite this article

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Abstract

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin receptor kinase B (TrkB), have a well-established role as regulators of synaptic plasticity, dendritic outgrowth and spine formation. Previously, we reported that the association of postsynaptic density protein 95 (PSD-95) with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCĪ³ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of neurodevelopmental disorders (NDDs). To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the Ube3a exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrate improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. A pharmacokinetic analysis of D-Syn3 demonstrates that it crosses the blood-brain barrier (BBB), and the brain influx rate is in the range of CNS therapeutics. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.

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Fig. 1: Targeting BDNF signaling.
Fig. 2: Syn3 and D-Syn3 restore synaptic plasticity in hippocampal slices of compound-injected AS mice.
Fig. 3: AS mice demonstrate increased seizure susceptibility across standard Racine scoring stages.
Fig. 4: Syn3 and D-Syn3 administered in WT mice demonstrated reduced seizure susceptibility in the latency to generalized clonic-tonic seizure stage, from the Racine Score.
Fig. 5: Subjects were evaluated for learning and memory abilities using the novel object recognition test.
Fig. 6: Accelerating rotarod was used to evaluate motor coordination and motor learning.

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Acknowledgements

We thank the Angelman Syndrome community and the UC Davis MIND Institute for supporting this research. We also thank Dr. Nathaniel Hodgson (IDDRC Animal Behavior and Physiology Core) for performing microdialysis and Rory (Dallon) Martin for exceptional husbandry and attention to the mouse colonies of the Silverman Laboratory and the IDDRC mouse behavioral core at the MIND Institute at UC Davis School of Medicine.

Funding

This work was supported by the National Institutes of Health [R01NS097808 (JLS), R01NS094440 (JM), R21MH104252 (JM), the Harrington Discovery Institute (JM), theĀ MIND Instituteā€™s Intellectual and Developmental Disabilities Resource Center (IDDRC), Grant/Award P50 HD103526 (PI, Abbeduto)Ā and by generous funding from the Foundation for Angelman Syndrome Therapeutics (JM and XY)]. We also thank the IDDRC Animal Behavior and Physiology Core, funded by NIH/NICHD P50 HD105351.

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  1. These authors contributed equally: Jill L. Silverman, John Marshall.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California Davis School of Medicine, 4625 2nd Avenue Suite 1001A, Sacramento, CA, 95817, USA

    Emily Z. Huie,Ā Kyle Tran,Ā Emma R. Monsen,Ā Anna Y. YotovaĀ &Ā Jill L. Silverman

  2. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02912, USA

    Xin Yang,Ā Mengia S. Rioult-Pedotti,Ā Mandar Naik,Ā Yu-Wen Alvin HuangĀ &Ā John Marshall

  3. Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, 98108, USA

    Kim Hansen,Ā Michelle A. EricksonĀ &Ā William A. Banks

  4. Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Department of Medicine, Seattle, WA, 98104, USA

    Kim Hansen,Ā Michelle A. EricksonĀ &Ā William A. Banks

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JLS and JM designed the study. EZH and ERM generated the mice through paternal and maternal specific breeding lines and performed genotyping to identify mice for groups. EZH, KT, and AYY performed the behavioral experiments and subsequent analyses. XY and YAH conducted the biochemistry and signaling studies in the iPSC cells. MSP conducted the LTP analysis. MN completed the structural biology analysis. KH, MAE and WAB conducted the pharmacokinetic studies. JM and JLS supervised the study and interpretations of data. EZH, JM, and JLS drafted the initial manuscript. All authors included valuable comments and edits to the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jill L. Silverman or John Marshall.

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Huie, E.Z., Yang, X., Rioult-Pedotti, M.S. et al. Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model. Neuropsychopharmacol. 50, 772ā€“782 (2025). https://doi.org/10.1038/s41386-024-02020-z

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