Highlights
- •RORα dysfunction resulted in selective lowering of DHA in cerebellum.
- •Dietary supplementation of EPA and DHA did not rescue lower DHA concentrations and compositions in RORα-deficient mice.
- •The effect of RORα on n-3 PUFA metabolism was region-specific and age-dependent.
Abstract
Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well
as in learned motor deficits, cognition impairments and perseverative tendencies that
are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on
brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim
of this study is to examine the effects of RORα deficiency on brain phospholipid fatty
acid concentrations and compositions. Staggerer mice (Rorasg/sg) and wildtype littermates (Rora+/+) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were
quantified by gas chromatography-flame ionization detection. In the cerebellum, all
fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid
concentrations were significantly different at 2-month-old, we examined changes in
fatty acid composition. The composition of ARA was not significantly different between
genotypes; though DHA composition remained significantly lowered. Despite cerebellar
atrophy at >7-months-old, cerebellar fatty acid concentrations had recovered comparably
to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during
neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific
and age-dependent.
Keywords
Abbreviations:
ALA (alpha-linolenic acid), ASD (autism spectrum disorder), DPA (docosapentaenoic acid), EPA (eicosapentaenoic acid)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Prostaglandins, Leukotrienes and Essential Fatty AcidsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Staggerer, a new mutation in the mouse affecting the cerebellum.Science. 1962; 137: 610-612
- Role of staggerer gene in determining cell number in cerebellar cortex. I. Granule cell death is an indirect consequence of staggerer gene action.Brain Res. 1983; 313: 267-274
- Staggerer chimeras: intrinsic nature of Purkinje cell defects and implications for normal cerebellar development.Brain Res. 1979; 178: 443-457
- Purkinje cell fate in staggerer mutants: agenesis versus cell death.J. Neurobiol. 2000; 42: 323-337
- Developmental mechanism for changes in cerebellum of "staggerer" mouse, a neurological mutant of genetic origin.Neurology. 1972; 22: 743-754
- Electron microscopic analysis of postnatal histogenesis in the cerebellar cortex of staggerer mutant mice.J. Comp. Neurol. 1978; 179: 831-863
- Transsynaptic degeneration 'en cascade' in the cerebellar cortex of staggerer mutant mice.Brain Res. 1974; 67: 519-526
- Cerebellar Purkinje cell loss during life span of the heterozygous staggerer mouse (Rora(+)/Rora(sg)) is gender-related.J. Comp. Neurol. 1999; 411: 267-273
- Progressive atrophy of cerebellar Purkinje cell dendrites during aging of the heterozygous staggerer mouse (Rora(+/sg)).Brain Res. Dev. Brain Res. 2001; 126: 201-209
- Neuronal cell loss in heterozygous staggerer mutant mice: a model for genetic contributions to the aging process.Brain Res. Dev. Brain Res. 1992; 67: 153-160
- Retinoid-related orphan receptor alpha controls the early steps of Purkinje cell dendritic differentiation.J. Neurosci. 2006; 26: 1531-1538
- Early postnatal Purkinje cells from staggerer mice undergo aberrant development in vitro with characteristic morphologic and gene expression abnormalities.Brain Res. Dev. Brain Res. 2004; 152: 153-157
- A comparative study of Purkinje cells in two RORalpha gene mutant mice: staggerer and RORalpha(-/-).Brain Res. Dev. Brain Res. 2001; 127: 165-174
- Role of the Staggerer gene in determining Purkinje cell number in the cerebellar cortex of mouse chimeras.Brain Res. 1981; 227: 475-485
- Neuronal differentiation and developmental characteristics in the dentate gyrus of staggerer mutant mice.BMB Rep. 2010; 43: 122-126
- Disruption of the nuclear hormone receptor RORalpha in staggerer mice.Nature. 1996; 379: 736-739
- Orphan nuclear receptor ROR alpha-deficient mice display the cerebellar defects of staggerer.Mech. Dev. 1998; 70: 147-153
- Tissue-based map of the human proteome.Science. 2015; 3471260419
- staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice.Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3960-3965
- Molecular mechanism regulating 24-hour rhythm of dopamine D3 receptor expression in mouse ventral striatum.Mol. Pharmacol. 2013; 83: 959-967
- An orphan nuclear receptor, mROR alpha, and its spatial expression in adult mouse brain.Brain Res. Mol. Brain Res. 1995; 33: 217-226
- Immunohistochemical characterization of the orphan nuclear receptor ROR alpha in the mouse nervous system.J. Histochem. Cytochem. 2004; 52: 311-323
- Prominent expression of nuclear hormone receptor ROR alpha in Purkinje cells from early development.Neurosci. Res. 1997; 28: 177-184
- The nuclear receptor ROR(alpha) exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 21365-21370
- Mature Purkinje cells require the retinoic acid-related orphan receptor-alpha (RORalpha) to maintain climbing fiber mono-innervation and other adult characteristics.J. Neurosci. 2013; 33: 9546-9562
- RORalpha regulates multiple aspects of dendrite development in cerebellar Purkinje cells in Vivo.J. Neurosci. 2015; 35: 12518-12534
- Cell-autonomous and non-cell-autonomous neuroprotective functions of RORalpha in neurons and astrocytes during hypoxia.J. Neurosci. 2011; 31: 14314-14323
- Structural and immunohistological modifications in olfactory bulb of the staggerer mutant mouse.Biol. Cell. 1999; 91: 29-44
- Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain.FASEB J. 2010; 24: 3036-3051
- Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder.Mol. Autism. 2013; 4: 14
- Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism.PLoS One. 2011; 6: e17116
- Retinoic acid-related orphan receptor alpha (RORA) variants are associated with autism spectrum disorder.Metab. Brain Dis. 2017; 32: 1595-1601
- Circadian genes and lithium response in bipolar disorders: associations with PPARGC1A (PGC-1alpha) and RORA.Genes Brain Behav. 2016; 15: 660-668
- Genetic association study of circadian genes with seasonal pattern in bipolar disorders.Sci. Rep. 2015; 5: 10232
- Investigation of associations between NR1D1, RORA and RORB genes and bipolar disorder.PLoS One. 2015; 10e0121245
- Association between circadian genes, bipolar disorders and chronotypes.Chronobiol. Int. 2014; 31: 807-814
- Retinoid-related orphan receptor alpha (RORA) gene variation is associated with trait depression.Psychiatry Res. 2015; 229: 629-630
- Associations of PER3 and RORA circadian gene polymorphisms and depressive symptoms in older adults.Am. J. Geriatr. Psychiatry. 2015; 23: 1075-1087
- RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response.Trans. Psychiatry. 2015; 5: e538
- Genome-wide association scan of trait depression.Biol. Psychiatry. 2010; 68: 811-817
- The cerebellum and psychiatric disorders.Front Public Health. 2015; 3: 66
- Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism.Autism. Res. 2009; 2: 78-97
- The neuropsychiatry of the cerebellum - insights from the clinic.Cerebellum. 2007; 6: 254-267
- [Role of the cerebellum in cognitive and behavioural control: scientific basis and investigation models].Acta Med. Port. 2006; 19: 257-267
- Cerebellar damage produces selective deficits in verbal working memory.Brain. 2006; 129: 306-320
- Is the cerebellum relevant in the circuitry of neuropsychiatric disorders?.J. Psychiatry Neurosci. 2005; 30: 178-186
- An emerging concept. The cerebellar contribution to higher function.Arch. Neurol. 1991; 48: 1178-1187
- Motor behavior of heterozygous staggerer mutant (+/sg) versus normal (+/+) mice during aging.Behav. Brain Res. 1995; 72: 97-102
- Performance of normal and neurological mutant mice on radial arm maze and active avoidance tasks.Behav. Neural Biol. 1986; 46: 216-226
- Exploration and spatial learning in staggerer mutant mice.J. Neurogenet. 1987; 4: 285-291
- Discrimination learning in RORA(sg) and Grid2(ho) mutant mice.Neurobiol. Learn. Mem. 2008; 90: 472-474
- The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants.Lipids. 2003; 38: 303-315
- Essential fatty acids and the brain.Can. J. Psychiatry. 2003; 48: 195-203
- The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina.Prog. Lipid Res. 2001; 40: 1-94
- Tissue levels of polyunsaturated fatty acids during early human development.J. Pediatr. 1992; 120: S129-S138
- The influence of dietary docosahexaenoic acid and arachidonic acid on central nervous system polyunsaturated fatty acid composition.Prostaglandins Leukot. Essent. Fatty Acids. 2007; 77: 247-250
- The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system.BMC Med. 2005; 3: 11
- Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3.Nature. 2006; 440: 813-817
- N-Docosahexaenoylethanolamine: a neurotrophic and neuroprotective metabolite of docosahexaenoic acid.Mol. Aspects Med. 2018; 64: 34-44
- Altered expression of key dopaminergic regulatory proteins in the postnatal brain following perinatal n-3 fatty acid dietary deficiency.J. Neurochem. 2008; 106: 662-671
- Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.Nutrition. 2013; 29: 1175-1185
- The neurobiology of lipid metabolism in autism spectrum disorders.Neurosignals. 2010; 18: 98-112
- Dietary docosahexaenoic acid alleviates autistic-like behaviors resulting from maternal immune activation in mice.Prostaglandins Leukot. Essent. Fatty Acids. 2016; 106: 27-37
- Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism.Neuropharmacology. 2008; 54: 901-911
- Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long-Evans rat: further development of a rodent model of autism.Behav. Brain Res. 2009; 200: 33-41
- Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha.J. Biol. Chem. 2001; 276: 2865-2871
- Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor RORalpha.Circulation. 1998; 98: 2738-2743
- Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor RORalpha.J. Biol. Chem. 1997; 272: 22401-22404
- The orphan nuclear receptor, RORalpha, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity.J. Biol. Chem. 2008; 283: 18411-18421
- RORalpha controls hepatic lipid homeostasis via negative regulation of PPARgamma transcriptional network.Nat. Commun. 2017; 8: 162
- Sex differences in the brain: implications for explaining autism.Science. 2005; 310: 819-823
- Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain.Sci. Rep. 2015; 5: 15791
- Internet survey of treatments used by parents of children with autism.Res. Dev. Disabil. 2006; 27: 70-84
- Dietary DHA during development affects depression-like behaviors and biomarkers that emerge after puberty in adolescent rats.J. Lipid Res. 2015; 56: 151-166
- Omega-3 fatty acid deficiency during brain maturation reduces neuronal and behavioral plasticity in adulthood.PLoS One. 2011; 6: e28451
- Exposure to a maternal n-3 fatty acid-deficient diet during brain development provokes excessive hypothalamic-pituitary-adrenal axis responses to stress and behavioral indices of depression and anxiety in male rat offspring later in life.J. Nutr. Biochem. 2013; 24: 70-80
- Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration.J. Neurochem. 2000; 75: 2563-2573
- Behavioral responses are altered in piglets with decreased frontal cortex docosahexaenoic acid.J. Nutr. 2003; 133: 3222-3227
- Deficit in prepulse inhibition in mice caused by dietary n-3 fatty acid deficiency.Behav. Neurosci. 2009; 123: 1218-1225
- Effects of omega-3 fatty acids on stereotypical behavior and social interactions in Wistar rats prenatally exposed to lipopolysaccarides.Nutrition. 2017; 35: 119-127
- Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice.Neuropharmacology. 2015; 90: 15-22
- DHA mitigates autistic behaviors accompanied by dopaminergic change in a gene/prenatal stress mouse model.Neuroscience. 2018; 371: 407-419
- Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice.Eur. Neuropsychopharmacol. 2019; 29: 16-31
- Maternal fish oil supplementation affects the social behavior, brain fatty acid profile, and sickness response of piglets.J. Nutr. 2015; 145: 2176-2184
- Relationship between long chain n-3 polyunsaturated fatty acids and autism spectrum disorder: systematic review and meta-analysis of case-control and randomised controlled trials.Nutrients. 2017; 9 (pii: E155)
- A pilot randomized controlled trial of omega-3 fatty acids for autism spectrum disorder.J. Autism Dev. Disord. 2011; 41: 545-554
- Dietary docosahexaenoic acid supplementation in children with autism.J. Pediatr. Gastroenterol. Nutr. 2014; 58: 715-722
- A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism.Mol. Autism. 2015; 6: 18
Article info
Publication history
Published online: November 20, 2019
Accepted:
November 13,
2019
Received in revised form:
November 13,
2019
Received:
October 11,
2019
Identification
Copyright
© 2019 Published by Elsevier Ltd.
