A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition.
DISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous Disc1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired Disc1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.
Kvajo
Mirna
M
Department of Psychiatry, Columbia University Medical Center, 1051 Riverside Drive, New York, NY 10032, USA. mk2758@columbia.edu
McKellar
Heather
H
Arguello
P Alexander
PA
Drew
Liam J
LJ
Moore
Holly
H
MacDermott
Amy B
AB
Karayiorgou
Maria
M
Gogos
Joseph A
JA
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D003071:Cognition; D003072:Cognition Disorders / Q000473:pathology; D018891:Dentate Gyrus / Q000473:pathology; D004195:Disease Models, Animal; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity; D009474:Neurons / Q000473:pathology*; D017397:Prefrontal Cortex / Q000473:pathology; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D009435:Synaptic Transmission
C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins