Altered gene expression in early postnatal monoamine oxidase A knockout mice

Abstract

We reported previously that monoamine oxidase (MAO) A knockout (KO) mice show increased serotonin (5-hydroxytryptamine, 5-HT) levels and autistic-like behaviors characterized by repetitive behaviors, and anti-social behaviors. We showed that administration of the serotonin synthesis inhibitor para-chlorophenylalanine (pCPA) from post-natal day 1 (P1) through 7 (P7) in MAO A KO mice reduced the serotonin level to normal and reverses the repetitive behavior. These results suggested that the altered gene expression at P1 and P7 may be important for the autistic-like behaviors seen in MAO A KO mice and was studied here. In this study, Affymetrix mRNA array data for P1 and P7 MAO A KO mice were analyzed using Partek Genomics Suite and Ingenuity Pathways Analysis to identify genes differentially expressed versus wild-type and assess their functions and relationships. The number of significant differentially expressed genes (DEGs) varied with age: P1 (664) and P7 (3307) [false discovery rate (FDR) <0.05, fold-change (FC) >1.5 for autism-linked genes and >2.0 for functionally categorized genes]. Eight autism-linked genes were differentially expressed in P1 (upregulated: NLGN3, SLC6A2; down-regulated: HTR2C, MET, ADSL, MECP2, ALDH5A1, GRIN3B) while four autism-linked genes were differentially expressed at P7 (upregulated: HTR2B; downregulated: GRIN2D, GRIN2B, CHRNA4). Many other genes involved in neurodevelopment, apoptosis, neurotransmission, and cognitive function were differentially expressed at P7 in MAO A KO mice. This result suggests that modulation of these genes by the increased serotonin may lead to neurodevelopmental alteration in MAO A KO mice and results in autistic-like behaviors.

Perinatal MAO Inhibition Produces Long-Lasting Impairment of Serotonin Function in Offspring

“…Anatomically, MAO-A knockout mice have reduced levels of the serotonin transporter (SERT) in the dorsal raphe [ 17 ], as well as higher somatosensory and lower entorhinal cortical activation as compared to wildtype controls [ 21 ]. These anatomical alterations are accompanied with modified gene expression associated with neurodevelopment, apoptosis, and cognitive function which may be related to the behavioral and anatomical abnormalities reported with altered serotonin levels during development [ 22 ]. By contrast, MAO-B knockout mice display neither aberrant behavior nor detectable changes in monoamines, with the exception of increased levels of phenylethylamine [ 23 ].…”

“…Accompanying the neurochemical changes, these mice exhibit abnormal fear conditioning and alterations in hippocampal long-term potentiation [ 18 ]. Similar to the MAO-A knockout mice, MAO-A/B knockout mice display increased aggression and anxiety-like behaviors and have been proposed as a model of autism spectrum disorder [ 15 , 16 , 22 , 24 ].…”

Emerging evidence implicating a role for neurexins in neurodegenerative and neuropsychiatric disorders

“…Functional in vitro and in vivo studies have also found evidence for the roles of neurexins in ASD. Monoamine oxidase A knockout (KO) mice, which are an animal model for autism, exhibited downregulated levels of both neurexin 1 and neurexin 2 [55]. Furthermore, mice colonized with the microbiota of ASD patients showed differential splicing of NRXN2 [59].…”