Disc1 variation leads to specific alterations in adult neurogenesis.

Jayanth S Chandran,Ilias Kazanis,David J Porteous,Fumiaki Ogawa,Charles Ffrench-Constant,Steven J Clapcote,J Kirsty Millar

doi:10.1371/journal.pone.0108088

Abstract

Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate Disc1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain.

Highlights

Disrupted in schizophrenia 1 (DISC1) was originally identified as a gene disrupted by a balanced chromosomal translocation t(1;11)(q42.1;q14.3) in a large Scottish family with several major mental disorders including schizophrenia, bipolar disorder and recurrent major depressive disorder [1]
When we used this antibody on brain lysates from the DISC1 mice, we found no differences in DISC1 expression between the Disc131L/31L or Disc1100P/100P mice compared to age-matched wildtype controls (Figure 1A)
The majority of neurospheres are formed from cells expressing Hes5, which is expressed in neural stem cells and subsequently down regulated in more neuronally committed progenitors [16,17,18]

Summary

Introduction

DISC1 was originally identified as a gene disrupted by a balanced chromosomal translocation t(1;11)(q42.1;q14.3) in a large Scottish family with several major mental disorders including schizophrenia, bipolar disorder and recurrent major depressive disorder [1]. DISC1 is an intracellular scaffold protein that binds to a number of proteins contributing to different signaling pathways [2] These include interactions with GSK3b and phosphodiesterase 4 (PDE4) at the N-terminus, and NDEL1 and LIS1 at the C-terminus. Knockdown of DISC1 in mice leads to reduced cell proliferation and neuronal migration defects in the hippocampus due to perturbations in GSK3b and Ndel respectively [4,10]. These results suggest a hypothesis that alterations in DISC1 structure, either due to distinct mutations or individual variations, differentially affect downstream pathways, which might contribute to the different facets of psychiatric disease seen in patients with abnormalities in DISC1

Methods

Results

Conclusion