An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

Author:

Shih Yu-Tzu,Alipio Jason Bondoc,Sahay AmarORCID

Abstract

SUMMARYHeterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1aDyrk1agene 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 thatAblim3downregulation in dentate granule cells of adult hemizygousDyrk1amice 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 hemizygousDyrk1amice also rescued social recognition. Together, these findings illustrate how targeting Dyrk1a synaptic and circuit substrates as “enhancers of Dyrk1a function” harbors potential to reverseDyrk1ahaploinsufficiency-associated circuit and cognition impairments.HighlightsDyrk1a in mossy fibers recruits PV IN mediated feed-forward inhibition of CA3 and CA2Dyrk1a-Ablim3 signaling in mossy fiber-PV IN synapses promotes inhibition of CA3 and CA2DownregulatingAblim3restores PV IN excitability, CA3/CA2 inhibition and social recognition inDyrk1a+/-miceChemogenetic activation of PV INs in CA3/CA2 rescues social recognition inDyrk1a+/-mice

Publisher

Cold Spring Harbor Laboratory

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