# Hippocampal synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $604,650

## Abstract

Project Summary/Abstract
Autism spectrum disorder (ASD) is a class of heterogeneous neurodevelopmental disorders that
affects 1 in 54 children in the United States and is characterized by impaired social cognition,
repetitive behaviors and seizure risk. Genetic studies and large-scale exome-sequencing efforts
have identified haplo-insufficient loss of function (LOF) mutations in the Dual specificity
tyrosine-phosphorylation-regulated kinase Dyrk1a gene in syndromic ASD. However, the
functional impact of hemizygous Dyrk1a LOF on synaptic and circuit mechanisms underlying
social cognition remain poorly understood. This challenge is magnified because Dyrk1a
phosphorylates >70 substrates and Dyrk1a LOF is likely to disrupt many biological processes
during development. Currently, there are no drugs that enhance or restore Dyrk1a function.
Together, these observations underscore the need to identify cell-type and circuit-specific
mechanisms that maybe targeted to reverse Dyrk1a associated social cognition impairments. This
proposal seeks to bridge these gaps by identifying a Dyrk1a-dependent synaptic and circuit
mechanism mediating social recognition that can be targeted in adulthood to reverse
developmental loss of Dyrk1a-associated impairments in social cognition circuitry and behavior.
The proposed Aims will build on our in vivo functional genetic epistasis analysis of Dyrk1a and
one of its substrates, Ablim3, in hippocampal mossy fibers to test the role of this pathway in
reversing circuit and social recognition memory impairments in adult Dyrk1a hemizygous mice
that models Dyrk1a haploinsufficiency in ASD. Execution of the Aims harbors potential to guide
gene therapy strategies targeting molecular and circuit substrates of Dyrk1a, Ablim3 and
parvalbumin inhibitory neuron mediated GABAergic inhibition, in the adult brain as “Dyrk1a
enhancers” to rescue social cognition impairments in ASD resulting from Dyrk1a
haploinsufficiency.

## Key facts

- **NIH application ID:** 10900444
- **Project number:** 5R01MH131652-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Amar Sahay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $604,650
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900444

## Citation

> US National Institutes of Health, RePORTER application 10900444, Hippocampal synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition (5R01MH131652-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900444. Licensed CC0.

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