Disturbed neurotransmitter homeostasis in ether lipid deficiency

Abstract

Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase ( Gnpat ) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters. In the dopaminergic nigrostriatal tract, synaptic endings but not neuronal cell bodies were affected. Neurotransmitter turnover was altered in ether lipid-deficient murine as well as human post-mortem brain tissue. A generalized loss of synapses did not account for the neurotransmitter deficits, since the levels of several presynaptic proteins appeared unchanged. However, reduced amounts of vesicular monoamine transporter indicate a compromised vesicular uptake of neurotransmitters. As exemplified by norepinephrine, the release of neurotransmitters from Gnpat KO brain slices was diminished in response to strong electrical and chemical stimuli. Finally, addressing potential phenotypic correlates of the disturbed neurotransmitter homeostasis, we show that ether lipid deficiency manifests as hyperactivity and impaired social interaction. We propose that the lack of ether lipids alters the properties of synaptic vesicles leading to reduced amounts and release of neurotransmitters. These features likely contribute to the behavioral phenotype of Gnpat KO mice, potentially modeling some human neurodevelopmental disorders like autism or attention deficit hyperactivity disorder.

Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata

“…Effect of synthetic plasmalogen treatment on the behavior of Pex7 hypo/null mice All four experimental mouse cohorts were subjected to the open field test before treatment (baseline) and at the end of the treatment period. A similar RCDP2 mouse model, based on a knockout of the Gnpat gene, had previously been demonstrated to be hyperactive in the open field test (Dorninger et al, 2019). In the untreated Pex7 hypo/null mice, we also demonstrated similar hyperactivity in the open field test in both young and older mice (data not shown).…”

“…Behavioral assessments in RCDP mouse models are limited due to early development of cataracts, which impact the visual abilities of the mice. Hyperactivity in the open field test has been reproducible in different RCDP mouse models (Dorninger et al, 2019). Furthermore, it is a potentially clinically useful behavioral phenotype as it has been reported in patients with mild RCDP disease (Yu et al, 2013).…”

“…In many tissues, the majority of the glycerophosphoethanloamine fraction is PlsEtn (Braverman and Moser, 2012;Brites et al, 2004). Plasmalogens are essential for the architecture of lipid membranes and are critical for physiological processes such as vesicular fusion (Dorninger et al, 2019;Glaser and Gross, 1994;Lohner et al, 1991), membrane protein activity (da Silva et al, 2014;Dorninger et al, 2019;Wood et al, 2011b) and protection against oxidation (Kuczynski and Reo, 2006;Luoma et al, 2015). Reduced PlsEtn levels are one of the main biochemical features of peroxisome biogenesis disorders, including RCDP and Zellweger spectrum disorders, and were also reported in other diseases such as Alzheimer's disease (Goodenowe et al, 2007;Han et al, 2001;Kou et al, 2011;Wood et al, 2010), Parkinson's disease (Dragonas et al, 2009;Fabelo et al, 2011), schizophrenia (Kaddurah-Daouk et al, 2012), Down syndrome (Murphy et al, 2000) and Gaucher disease (Moraitou et al, 2014).…”

On the road to unraveling the molecular functions of ether lipids

“…Finally, structural alterations in caveolae, clathrincoated pits, ER and Golgi apparatus have been reported in the absence of ether lipids, which hits towards a role for these lipids in the general architecture of the endomembrane system [79]. A more recent paper from the same group has pointed out the role of ether lipids in the release of neurotransmitters, which could contribute to the behavioral phenotype of ether lipid-deficient mice [80].…”

Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease

“…Indeed, more generally, a modification of EL amounts influences neurotransmitter synthesis and their release. In a GNPAT KO mouse model, a decrease in both the quantity and release of dopamine in the striatum has been observed, leading to hyperactive mice, with a loss of social interaction and fear conditioning (31). In contrast to Parkinson's disease, in a schizophrenia or bipolar depression context, the level of Pls in the frontal cortex of patients was found to be higher than in control patients (32), which illustrates the fine equilibrium of EL quantity necessary for excitation-secretion coupling.…”