Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

Abstract

We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia.

Influence of glutamate and GABA transport on brain excitatory/inhibitory balance

“…254 Furthermore, mice with EAAT3/EAAC1 haploinsufficiency show biochemical, behavioral, and histological changes that reflect an altered redox state, congruous with changes found in patients with schizophrenia. 255 Finally, genetic linkage and association studies performed in obsessive convulsive disorder (OCD), itself linked with cortical excitability abnormalities, 256 point to gene variants in Slc1a1 (for review see Escobar et al 257 ). While mice null for EAAT3 do not show behaviors consistent with OCD, overexpression of EAAT3 in forebrain neurons alone does result in anxiety-like and repetitive behaviors, which are also often reported in persons diagnosed with OCD.…”

Transmembrane protease, serine 4 (TMPRSS4) is upregulated in IPF lungs and increases the fibrotic response in bleomycin-induced lung injury

“…Interestingly, we do not observe a gene-dose effect. There are several examples in the literature demonstrating that in some cases haploinsufficient mice behave very similar to completely deficient mice indicating a dominant effect of the haploinsufficiency [ 36 , 37 ]. Similar to IPF, in the mouse model of lung fibrosis TMPRSS4 was also observed in epithelial cells and more strongly in mast cells.…”

Behavioral Tasks Evaluating Schizophrenia-like Symptoms in Animal Models: A Recent Update

“…Such conditions include Sterol regulatory element-binding protein 1c (SREBP1c) knockout (KO) mice [ 47 ], G protein-coupled receptor 88 (GPR88) KO mice [ 48 ], dystrobrevin binding protein 1 (Dtnbp1) deficiency mice [ 49 ], knockdown of metabotropic glutamate receptor 5 (mGluR 5) mice [ 50 ], N-methyl-D-aspartate (NMDA) receptor ablation mice [ 51 ], brain-specific collapsin response mediator protein 2 (CRMP2) KO mice [ 52 ], lq21.1 hemizygous microdeletion (hemizygotic Df(h1q21)/ +) mice + amphetamine [ 53 ], dopamine transporter (DAT) KO mice [ 54 ], and glial glutamate and aspartate transporter (GLAST) KO mice [ 55 ]. However, no effect on locomotor activity was observed in animal models with reduced solute carrier family 1 member 1 (SLC1A1) expression [ 56 ], growth arrest-specific 7 (GAS7) deficiency mice [ 57 ] (however, this model has decreased sensorimotor gating, as measured by PPI), type III neuregulin-1 (NRG1) +/− male mice from mutant fathers [ 58 ] (however, this model has increased sociability in the three-chamber test), and selective knockdown mice of phospholipase C-β1 (PLC-β1) in the medial prefrontal cortex (mPFC) [ 59 ]. Pharmacologically, several drugs, including amphetamine and MK-801 (NMDA receptor (NMDAR) antagonist) increase locomotor activity but can inversely lead to a decrease at higher doses due to sedative and anesthetic effects [ 23 ].…”