Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia.
Akira SobueItaru KushimaTaku NagaiWei ShanTakao KohnoBranko AleksicYuki AoyamaDaisuke MoriYuko AriokaNaoko KawanoMaeri YamamotoMitsuharu HattoriToshitaka NabeshimaKiyofumi YamadaNorio OzakiPublished in: Scientific reports (2018)
Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.
Keyphrases
- copy number
- genome wide
- high fat diet induced
- extracellular matrix
- high resolution
- mitochondrial dna
- healthcare
- white matter
- traumatic brain injury
- type diabetes
- single cell
- early onset
- metabolic syndrome
- mental health
- mass spectrometry
- dna methylation
- binding protein
- adipose tissue
- cerebral ischemia
- small molecule
- amino acid
- wild type
- young adults
- drug induced
- insulin resistance
- high speed