Journal
JOURNAL OF NEUROSCIENCE
Volume 41, Issue 37, Pages 7768-7778Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3148-20.2021
Keywords
AMPA Receptor; dendritic spine; glutamatergic synapse; neurodevelopmental disorder; NMDA Receptor; RhoGEF
Categories
Funding
- Brain and Behavior Research Foundation
- Simons Foundation
- McKnight Foundation
- National Institute of Mental Health [R00MH103398]
- National Institute of Neurological Disorders and Stroke [R01NS112480]
- University of Southern California Theodore and Wen-Hui Chen Endowed Fellowship
- National Institute of Neurological Disorders and Stroke Intramural Research Program
Ask authors/readers for more resources
The study identified that mutations in the Trio protein can affect its interaction with Neuroligin 1, leading to disrupted synaptogenesis and aberrant glutamatergic neurotransmission. These mutations not only increase synaptogenesis, but may also decrease the effects of NLGN-mediated glutamatergic neurotransmission.
We recently identified an autism spectrum disorder/intellectual disability (ASD/ID)-related de novo mutation hotspot in the Rac1-activating GEF1 domain of the protein Trio. Trio is a Rho guanine nudeotide exchange factor (RhoGEF) that is essential for glutamatergic synapse function. An ASD/ID-related mutation identified in Trio's GEF1 domain, Trio D1368V, produces a pathologic increase in glutamatergic synaptogenesis, suggesting that Trio is coupled to synaptic regulatory mechanisms that govern glutamatergic synapse formation. However, the molecular mechanisms by which Trio regulates glutamatergic synapses are largely unexplored. Here, using biochemical methods, we identify an interaction between Trio and the synaptogenic protein Neuroligin 1 (NLGN1) in the brain. Molecular biological approaches were then combined with super-resolution dendritic spine imaging and whole-cell voltage-damp electrophysiology in hippocampal slices from male and female rats to examine the impact ASD/ID-related Trio mutations have on NLGN1-mediated synaptogenesis. We find that an ASD/ID-related mutation in Trio's eighth spectrin repeat region, Trio N1080I, inhibits Trio's interaction with NLGN1 and prevents Trio D1368V-mediated synaptogenesis. Inhibiting Trio's interaction with NLGN1 via Trio N1080I blocked NLGN1-mediated synaptogenesis and increases in synaptic NMDA Receptor function but not NLGN1-mediated increases in synaptic AMPA Receptor function. Finally, we show that the aberrant synaptogenesis produced by Trio D1368V is dependent on NLGN signaling. Our findings demonstrate that ASD/ID-related mutations in Trio are able to pathologically increase as well as decrease NLGN-mediated effects on glutamatergic neurotransmission, and point to an NLGN1-Trio interaction as part of a key pathway involved in ASD/ID etiology.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available