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

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Altered innate immune system status is observed in neurodegenerative diseases.
• Triggering receptor expressed in myeloid cells 2 (TREM2) variants are strongly associated with Alzheimer's disease (AD) and other neurodegenerative conditions.
• Understanding TREM2's in vivo function is critical for neurodegenerative disease research.

Purpose of the Study:

• To investigate the behavioral and cognitive functions of wild-type (WT) and Trem2 knockout (KO) mice.
• To analyze brain function under basal conditions and after innate immune stimulation with lipopolysaccharide (LPS).
• To identify transcriptomic alterations in Trem2-/- mice.

Main Methods:

• Comparative behavioral and cognitive testing of WT and Trem2-/- mice.
• Innate immune stimulation using peripheral lipopolysaccharide (LPS) administration.
• Transcriptomic analysis (RNA sequencing) of brain tissue at baseline and post-LPS.

Main Results:

• Neuroinflammation markers appeared before Aif1 and Trem2 upregulation post-LPS.
• Transcriptomic analysis revealed altered pathways in Trem2-/- mice.
• A specific Trem2-/- mouse line (Velocigene allele) exhibited exaggerated Treml1 upregulation, identified as an artifact.

Conclusions:

• The aberrant Treml1 upregulation in the Velocigene Trem2-/- line is an artifact, necessitating caution in interpreting functional studies with this specific model.
• Further research is needed to determine the functional relevance of the Treml1 transcriptional artifact.
• Other Velocigene alleles or targeting strategies require careful consideration of potential downstream gene effects.