Disrupted-in-Schizophrenia 1 (DISC1) Is Necessary for the Correct Migration of Cortical Interneurons

Abstract

Disrupted-in-Schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder.

A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex

“…However, other possibilities, such as altered interactions of cell surface receptors or different membrane dynamics in the presence or absence of polySia should be considered and explored in future studies. Reminiscent of the findings in polyST-deficient mice, altered precursor migration from the MGE and reduced numbers or loss of mainly PV interneurons in the postnatal cortex were observed in mouse models with deficiencies of NRG1/ERBB4 (Flames et al, 2004;Fisahn et al, 2009) or DISC1 (Hikida et al, 2007;Shen et al, 2008;Steinecke et al, 2012), which are among the most compelling schizophrenia risk genes in human (Ross et al, 2006), and in mice lacking the brain-derived neurotrophic factor receptor TRKB (also known as NTRK2) (Polleux et al, 2002) or the urokinase-type plasminogen activator receptor uPAR (also known as PLAUR) (Powell et al, 2001(Powell et al, , 2003. Collectively, these results indicate that compromised migration into the pallium causes reductions of specific interneuron populations in the cortex.…”

“…For example, longer leading processes have been observed in mice deficient for LIS1 and DISC1, in which impaired migration seems to be linked to altered nucleokinesis (Nasrallah et al, 2006;Steinecke et al, 2012). By contrast, ablation of either CXCR4 or CXCR7 chemokine receptor caused increased or reduced interneuron motility with longer or shorter leading processes, respectively (Wang et al, 2011).…”

“…Alterations of leading process morphology have been repeatedly linked to migration deficits (Nasrallah et al, 2006;Friocourt et al, 2007;Wang et al, 2011;Steinecke et al, 2012;Luccardini et al, 2013). To study the potential impact of polySia on the morphology of the leading process, coronal slices of E12.5 GAD67-GFP mice were cultured in the presence or absence of endo and the lengths of leading processes were evaluated after 1 day in vitro.…”

“…Reminiscent of clinical studies reporting interneuron alterations in the prefrontal cortex (PFC) of schizophrenic patients (Lewis et al, 2012;Marin, 2012), loss-of-function mouse models of major schizophrenia risk genes, such as NRG1 and DISC1, display defects in cortical interneuron development or altered interneuron numbers in the medial prefrontal cortex (mPFC) (Flames et al, 2004;Hikida et al, 2007;Shen et al, 2008;Steinecke et al, 2012). Motivated by these findings, and based on the well-known role of polySia in the migration of olfactory bulb interneurons (Ono et al, 1994;Chazal et al, 2000;Weinhold et al, 2005), we examined whether cortical interneurons, particularly those of the mPFC, would be affected by polySia deficiency.…”

EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence

“…The outgrowth assay was performed as described previously (Steinecke et al, 2012). For the dissection of explants from the DMS and the SMS, brains were cut into 225-μm coronal sections.…”