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Cell Rep. 2019 Mar 5;26(10):2805-2817.e9. doi: 10.1016/j.celrep.2019.02.022.

Trio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits.

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; Department of Neuroscience, Yale University, New Haven, CT 06510, USA.
2
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA.
3
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
4
Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA.
5
Model Animal Research Center, Nanjing University, Nanjing 210061, China.
6
Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; Department of Psychiatry, Yale University, New Haven, CT 06510, USA; Child Study Center, Yale University, New Haven, CT 06510, USA.
7
Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; Department of Neuroscience, Yale University, New Haven, CT 06510, USA; Department of Neurosurgery, Yale University, New Haven, CT 06510, USA.
8
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence (Fudan University), Ministry of Education, Shanghai 200433, China. Electronic address: xiaoxiao@fudan.edu.cn.
9
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA; Department of Neuroscience, Yale University, New Haven, CT 06510, USA. Electronic address: anthony.koleske@yale.edu.

Abstract

Heterozygous coding mutations in TRIO are associated with neurodevelopmental disorders, including autism, schizophrenia, bipolar disorder, and epilepsy, and impair TRIO's biochemical activities. To model mutant alleles, we ablated one or both Trio alleles from excitatory neurons in the cortex and hippocampus of mice. Trio haploinsufficiency increases anxiety and impairs social preference and motor coordination. Trio loss reduces forebrain size and dendritic arborization but increases dendritic spine densities. Cortical synapses in Trio haploinsufficient mice are small, exhibit pre- and postsynaptic deficits, and cannot undergo long-term potentiation. Similar phenotypes are observed in Trio knockout mice. Overall, Trio haploinsufficiency causes severe disease-relevant deficits in behavior and neuronal structure and function. Interestingly, phosphodiesterase 4A5 (PDE4A5) levels are reduced and protein kinase A (PKA) signaling is increased when TRIO levels are reduced. Elevation of PDE4A5 and drug-based attenuation of PKA signaling rescue Trio haploinsufficiency-related dendritic spine defects, suggesting an avenue for therapeutic intervention for TRIO-related neurodevelopmental disorders.

KEYWORDS:

TRIO; anxiety; dendritic spine; haploinsufficiency; long-term potentiation; motor cortex; neurodevelopmental disorder; phosphodiesterase 4A5; social preference; triple functional domain protein

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