RRC ID 54169
Author Sobue A, Kushima I, Nagai T, Shan W, Kohno T, Aleksic B, Aoyama Y, Mori D, Arioka Y, Kawano N, Yamamoto M, Hattori M, Nabeshima T, Yamada K, Ozaki N.
Title Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia.
Journal Sci Rep
Abstract 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.
Volume 8(1)
Pages 13046
Published 2018-8-29
DOI 10.1038/s41598-018-31390-w
PII 10.1038/s41598-018-31390-w
PMID 30158644
PMC PMC6115412
MeSH Animals Applied Behavior Analysis Cell Adhesion Molecules, Neuronal / blood Cell Adhesion Molecules, Neuronal / deficiency* Codon, Nonsense Extracellular Matrix Proteins / blood Extracellular Matrix Proteins / deficiency* Humans Mice Models, Animal Nerve Tissue Proteins / blood Nerve Tissue Proteins / deficiency* Neuropsychological Tests Reelin Protein Schizophrenia / genetics* Schizophrenia / pathology Schizophrenia / physiopathology* Sequence Deletion Serine Endopeptidases / blood Serine Endopeptidases / deficiency*
IF 3.998
Times Cited 9
Mice RBRC00063