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An inhibitory circuit-based enhancer of Dyrk1a function reverses Dyrk1a-associated impairment in social recognition

Yu-Tzu Shih, Jason Bondoc Alipio, View ORCID ProfileAmar Sahay
doi: https://doi.org/10.1101/2023.02.03.526955
Yu-Tzu Shih
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston
2Harvard Stem Cell Institute, Cambridge
3Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
4BROAD Institute of Harvard and MIT, Cambridge, United States
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Jason Bondoc Alipio
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston
2Harvard Stem Cell Institute, Cambridge
3Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
4BROAD Institute of Harvard and MIT, Cambridge, United States
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Amar Sahay
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston
2Harvard Stem Cell Institute, Cambridge
3Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
4BROAD Institute of Harvard and MIT, Cambridge, United States
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  • ORCID record for Amar Sahay
  • For correspondence: asahay@mgh.harvard.edu
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SUMMARY

Heterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1a Dyrk1a gene define a syndromic form of Autism Spectrum Disorder. The synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which Dyrk1a recruits feedforward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, Ablim3, as a synaptic substrate of Dyrk1a. We demonstrate that Ablim3 downregulation in dentate granule cells of adult hemizygous Dyrk1a mice is sufficient to restore PV IN mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult hemizygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting Dyrk1a synaptic and circuit substrates as “enhancers of Dyrk1a function” harbors potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.

Highlights Dyrk1a in mossy fibers recruits PV IN mediated feed-forward inhibition of CA3 and CA2

Dyrk1a-Ablim3 signaling in mossy fiber-PV IN synapses promotes inhibition of CA3 and CA2

Downregulating Ablim3 restores PV IN excitability, CA3/CA2 inhibition and social recognition in Dyrk1a+/- mice

Chemogenetic activation of PV INs in CA3/CA2 rescues social recognition in Dyrk1a+/- mice

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 03, 2023.
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An inhibitory circuit-based enhancer of Dyrk1a function reverses Dyrk1a-associated impairment in social recognition
Yu-Tzu Shih, Jason Bondoc Alipio, Amar Sahay
bioRxiv 2023.02.03.526955; doi: https://doi.org/10.1101/2023.02.03.526955
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An inhibitory circuit-based enhancer of Dyrk1a function reverses Dyrk1a-associated impairment in social recognition
Yu-Tzu Shih, Jason Bondoc Alipio, Amar Sahay
bioRxiv 2023.02.03.526955; doi: https://doi.org/10.1101/2023.02.03.526955

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