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Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.

ABSTRACT: It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that triggering receptor expressed in myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer's disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2-/- (KO) mice during basal conditions and brain function in the context of innate immune stimulation with peripherally administered lipopolysaccharide (LPS). Early markers of neuroinflammation preceded Aif1 and Trem2 upregulation that occurred at later stages (24-48?h post-LPS). We performed a transcriptomic study of these cohorts and found numerous transcripts and pathways that were altered in Trem2-/- mice both at baseline and 48?h after LPS challenge. Importantly, our transcriptome analysis revealed that our Trem2-/- mouse line (Velocigene allele) results in exaggerated Treml1 upregulation. In contrast, aberrantly high Treml1 expression was absent in the Trem2 knockout line generated by the Colonna lab and the Jackson Labs CRISPR/Cas9 Trem2 knockout line. Notably, removal of the floxed neomycin selection cassette ameliorated aberrant Treml1 expression, validating the artifactual nature of Treml1 expression in the original Trem2-/- Velocigene line. Clearly further studies are needed to decipher whether the Treml1 transcriptional artifact is functionally meaningful, but our data indicate that caution is warranted when interpreting functional studies with this particular line. Additionally, our results indicate that other Velocigene alleles or targeting strategies with strong heterologous promoters need to carefully consider downstream genes.

SUBMITTER: Kang SS

PROVIDER: S-EPMC5886290 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.

Kang Silvia S SS Kurti Aishe A Baker Kelsey E KE Liu Chia-Chen CC Colonna Marco M Ulrich Jason D JD Holtzman David M DM Bu Guojun G Fryer John D JD

Human molecular genetics 20180101 2

It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that triggering receptor expressed in myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer's disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2-/- (KO) mice during basal conditions and brain function ...[more]

PMID: 29040522

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Project description:BackgroundThe Latrophilin 3 (LPHN3) gene (recently renamed Adhesion G protein-coupled receptor L3 (ADGRL3)) has been linked to susceptibility to attention deficit/hyperactivity disorder (ADHD) and vulnerability to addiction. However, its role and function are not well understood as there are no known functional variants.MethodsTo characterize the function of this little known gene, we phenotyped Lphn3 null mice. We assessed motivation for food reward and working memory via instrumental responding tasks, motor coordination via rotarod, and depressive-like behavior via forced swim. We also measured neurite outgrowth of primary hippocampal and cortical neuron cultures. Standard blood chemistries and blood counts were performed. Finally, we also evaluated the transcriptome in several brain regions.ResultsBehaviorally, loss of Lphn3 increases both reward motivation and activity levels. Lphn3 null mice display significantly greater instrumental responding for food than wild-type mice, particularly under high response ratios, and swim incessantly during a forced swim assay. However, loss of Lphn3 does not interfere with working memory or motor coordination. Primary hippocampal and cortical neuron cultures demonstrate that null neurons display comparatively enhanced neurite outgrowth after 2 and 3 days in vitro. Standard blood chemistry panels reveal that nulls have low serum calcium levels. Finally, analysis of the transcriptome from prefrontal cortical, striatal, and hippocampal tissue at different developmental time points shows that loss of Lphn3 results in genotype-dependent differential gene expression (DGE), particularly for cell adhesion molecules and calcium signaling proteins. Much of the DGE is attenuated with age, and is consistent with the idea that ADHD is associated with delayed cortical maturation.ConclusionsTranscriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with both ADHD and addiction phenotypes. The data should further motivate analyses of Lphn3 function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development.

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Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.

Publications

Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.

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