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bioRxiv · 10.1101/2023.02.03.526955

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

Sahay, A.·Shi, Y.-T.·Alipio, J. B.
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Abstract

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. HighlightsDyrk1a 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

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Sahay, A., Shi, Y.-T., Alipio, J. B.. 2023-02-03. An inhibitory circuit-based enhancer of Dyrk1a function reverses Dyrk1a-associated impairment insocial recognition. https://doi.org/10.1101/2023.02.03.526955

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