2024
SELECTED PUBLICATIONS

JANUARY 2024

Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

Yevheniia Ishchenko, Amanda T. Jeng, Shufang Feng, Timothy Nottoli, Cindy Manriquez-Rodriguez, Khanh Nguyen, Melissa G. Carrizales, Matthew J. Vitarelli, Ellen E. Corcoran, Charles A. Greer, Samuel A. Myers, Anthony J. Koleske

Abstract

Heterozygosity for rare genetic variants in TRIO is associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal migration, synapse development and function. It remains unclear whether and how discrete TRIO variants differentially impact these neurodevelopmental events. Here, we elucidate how heterozygosity for NDD-associated Trio variants – +/K1431M (ASD), +/K1918X (SCZ), and +/M2145T (bipolar disorder, BPD) – impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for different Trio variants impacts motor, social, and cognitive behaviors in distinct ways that align with clinical phenotypes in humans. ASD- and SCZ-linked Trio variants differentially impact head and brain size with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although dendritic spine density and synaptic ultrastructure were only modestly altered in the Trio variant heterozygotes, we observe significant changes in synaptic function and plasticity including excitatory/inhibitory imbalance and long-term potentiation defects. We also identify distinct changes in glutamate synaptic release in +/K1431M and +/M2145T cortico-cortical synapses, associated with deficiencies in crucial presynaptic release regulators. While TRIO K1431M has impaired ability to promote GTP exchange on Rac1, +/K1431M mice exhibit increased Rac1 activity, suggesting possible compensation by other GEFs. Our work reveals that discrete disease-associated Trio variants yield overlapping but distinct NDD-associated phenotypes in mice and demonstrates, for the first time, an essential role for Trio in presynaptic glutamate release, underscoring the importance of studying the impact of variant heterozygosity in vivo.