This paper reports that reduced expression of DISC1 during late embryonic development (E15) impairs the migration of hippocampal pyramidal neurons into CA1, and disrupts the alignment and position of these neurons. Using in utero electroporation of RNAi against endogenous DISC1, the authors were able to disrupt hippocampal development and rescue the anatomical defects by expressing an RNAi-resistant DISC1. This paper provides further information about the important role of DISC1 in neuron migration during brain development, and is consistent with a number of similar studies of the cortex. Neuron migration problems have long been hypothesized to underlie the histopathological abnormalities seen in postmortem brain from patients with schizophrenia. This study and other recent work make it increasingly plausible to speculate that schizophrenia-associated variants in the DISC1 gene might affect the development of the cortex and hippocampus in patients with the disease.
It would be interesting to know the behavioral effects of DISC1 RNAi knockdown in the hippocampus, and to correlate these behavioral changes with the observed histological defects. The specific functional effect of histological abnormalities in the brains of people with schizophrenia remains unclear. Anatomically specific models such as the hippocampal electroporation used in this study could be very useful in this regard. Previous studies reporting on the biochemical and cellular effects of DISC1 knockdown in the cortex have shown impaired PPI, impaired novel object recognition, and increased amphetamine-induced locomotion (Niwa et al., 2010). It would be especially interesting to know if the hippocampal abnormalities affect spatial navigation and place-cell activation patterns (Harvey et al., 2009).
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K, Lu L, Tomisato S, Jaaro-Peled H, Seshadri S, Hiyama H, Huang B, Kohda K, Noda Y, O'Donnell P, Nakajima K, Sawa A, Nabeshima T. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron . 2010 Feb 25 ; 65(4):480-9. Abstract
Harvey CD, Collman F, Dombeck DA, Tank DW. Intracellular dynamics of hippocampal place cells during virtual navigation. Nature . 2009 Oct 15 ; 461(7266):941-6. Abstract
View all comments by Albert H. C. Wong