Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders

Abstract

Ether lipids form a specialized subgroup of phospholipids that requires peroxisomes to be synthesized. We have previously detected that deficiency in these lipids leads to a severe disturbance of neurotransmitter homeostasis and release as well as behavioral abnormalities, such as hyperactivity, in a mouse model. Here, we focused on a more detailed examination of the behavioral phenotype of ether lipid-deficient mice (Gnpat KO) and describe a set of features related to human psychiatric disorders. Gnpat KO mice show strongly impaired social interaction as well as nestlet shredding and marble burying, indicating disturbed execution of inborn behavioral patterns. Also, compromised contextual and cued fear conditioning in these animals suggests a considerable memory deficit, thus potentially forming a connection to the previously determined ether lipid deficit in human patients with Alzheimer’s disease. Nesting behavior and the preference for social novelty proved normal in ether lipid-deficient mice. In addition, we detected task-specific alterations in paradigms assessing depression- and anxiety-related behavior. The reported behavioral changes may be used as easy readout for the success of novel treatment strategies against ether lipid deficiency in ameliorating nervous system-associated symptoms. Furthermore, our findings underline that ether lipids are paramount for brain function and demonstrate their relevance for cognitive, social, and emotional behavior. We hereby substantially extend previous observations suggesting a link between deficiency in ether lipids and human mental illnesses, particularly autism and attention-deficit hyperactivity disorder.

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VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction

“…Additionally, decreased levels of total n-6, total phosphatidylethanolamine plasmalogens, and the n-6/n-3 ratio were observed in the brain of propionic acid infused ASD model rats [ 51 ]. Recent studies also demonstrate that glyceronephosphate O-acyltransferase ( Gnpat ) knockout mice, a model of complete deficiency in ether lipid biosynthesis including plasmalogens, displayed impaired social interaction, repetitive behavior, and hyperactivity, suggesting that plasmalogens may be involved in ASD-like behavior in mice [ 52 , 53 ]. Therefore, a future study of plasmalogen also is needed to understand the molecular mechanisms underlying lipid metabolism in ASD, particularly how they behave and have a role in PUFAs.…”

Plasmalogens, platelet-activating factor and beyond – Ether lipids in signaling and neurodegeneration

“…Furthermore, a genetic association between ether lipid biosynthesis and neurodevelopmental disorders has been revealed by two independent studies applying whole-exome sequencing ( Yu et al, 2013 ) and single nucleotide polymorphism analysis ( Ro et al, 2012 ). Recently, we could additionally strengthen the putative link by a series of behavioral analyses of a mouse model of ether lipid deficiency, indicating marked hyperactivity and signs of autistic behavior like stereotypy, impaired social interaction and highly abnormal marble burying behavior in Gnpat KO mice ( Dorninger et al, 2019a ; Dorninger et al, 2019b ).…”

“…In several recent publications, we have speculated about an association between neurodevelopmental disorders, particularly autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD), and ether lipids ( Dorninger et al, 2017a ; Dorninger et al, 2019a ; Dorninger et al, 2019b ). Indeed, there is growing evidence for an involvement of ether lipids in the pathophysiology of these diseases.…”