Trio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits

• DOI: 10.1016/j.celrep.2019.02.022
• Publication Date: 2019-03-05T16:09:34Z
• Authors: Sara Marie Katrancha; Juliana E. Shaw; Amy Y. Zhao; Samuel A. Myers; Alexandra R. Cocco; Amanda T. Jeng; Minsheng Zhu; Christopher Pitte...; Charles A. Greer; Steven A. Carr; Xiao Xiao; Anthony J. Koleske
• Keywords: Haploinsufficiency; Neurodevelopmental disorder

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