title: RNA expression profiling in brains of familial hemiplegic migraine type 1 knock-in mice.
abstract: BACKGROUND
  Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma-induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome.
  
  
  METHODS
  Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively.
  
  
  RESULTS
  Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain.
  
  
  CONCLUSIONS
  Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild-type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, The Netherlands.
authors.forename: Boukje
authors.initials: B
authors.lastname: de Vries
authors.forename: Else
authors.initials: E
authors.lastname: Eising
authors.forename: Ludo A M
authors.initials: LA
authors.lastname: Broos
authors.forename: Stephany C
authors.initials: SC
authors.lastname: Koelewijn
authors.forename: Boyan
authors.initials: B
authors.lastname: Todorov
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Peter A C 't
authors.initials: PA
authors.lastname: Hoen
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
mesh_terms: D000818:Animals; D001921:Brain / Q000503:physiopathology*; D020864:Calcium Channels, N-Type / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism; D002531:Cerebellum / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008881:Migraine Disorders / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D059467:Transcriptome / Q000235:genetics
chemical_list: D020864:Calcium Channels, N-Type; D009419:Nerve Tissue Proteins; D012313:RNA
keywords: CaV2.1 channel; FHM; cerebellum; cortex; gene expression; microarray; mutation