Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency

Abstract

Disrupted‐in‐Schizophrenia 1 (DISC1) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, we generated Disc1 mutant mice by introducing the 129S6/SvEv 25‐bp deletion Disc1 variants into the C57BL/6J strain. In this study, we used heterozygous Disc1 mutant (Het) mice to evaluate the DISC1 haploinsufficiency model of schizophrenia. No changes in locomotor behaviors were observed in Het mice; however, after amphetamine injection, greater locomotor activity was observed in Het mice compared with wild‐type (WT) mice. Moreover, amphetamine‐induced elevations of c‐Fos expression and dopamine level in the striatum were greater in Het mice than in WT controls, suggesting an altered dopaminergic regulation in the striatum of Het mice. Compared with those in WTs, the striatal protein levels of dopamine transporter and D2 dopamine receptor were increased in Het mice, while D1 dopamine receptor level was decreased. DISC1 interacting proteins, GSK3α and GSK3β, were downregulated in Het mice, whereas the levels of PDE4B and CREB were not altered. Morphologically, the complexities of striatal median spiny neurons (MSNs), parvalbumin‐positive interneurons and Iba1‐positive microglia were all decreased in Het mice. The density and head diameter of dendritic spines in the MSNs of Het mice were also reduced. Our results indicate that mice lacking one WT Disc1 allele are more sensitive to psychostimulant amphetamine challenge, which might be attributed to the altered structure and function of the striatal dopaminergic system. Here, we demonstrated striatal phenotypes in heterozygous Disc1 mutant mice, which could be a promising model of DISC1 haploinsufficiency.

Altered White Matter and Layer VIb Neurons in Heterozygous Disc1 Mutant, a Mouse Model of Schizophrenia

“…In the present study, we showed an increased density of NeuN-positive neurons in the white matter of Disc1 Het mice, a haploinsufficiency model of schizophrenia (Juan et al, 2014;Baskaran et al, 2020). This finding was in line FIGURE 6 | Morphometric analysis of Type II layer VIb neurons.…”

“…We had established a Disc1 mutant mouse model, in which a 25-bp deletion variant of 129S6/SvEv Disc1 gene was brought to the C57BL/6J background by generations of backcrossing (Juan et al, 2014). Compared with other Disc1 mutant mice, our model exhibits relatively moderate abnormalities, suggesting that these mice are in a prodromal status (Juan et al, 2014;Baskaran et al, 2020). This model is therefore suitable for studies concerning the impact of environmental risk factors.…”

Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model

“…We therefore suggest that our model might represent subjects in the prodromal states of SZ, in which predominant symptoms are not yet manifested [ 29 ]. In the following study, we further characterized the striatal phenotypes in Het Disc1 mice, an SZ model of haploinsufficiency [ 30 ]. We found biochemical and morphological changes in the striatum of Het Disc1 mice including the levels of dopamine (DA) receptors, GSK3, and PSD95 as well as the dendrites and spines of medium spiny neurons (MSNs) and density of parvalbumin (PV) neurons [ 30 ].…”

“…In the following study, we further characterized the striatal phenotypes in Het Disc1 mice, an SZ model of haploinsufficiency [ 30 ]. We found biochemical and morphological changes in the striatum of Het Disc1 mice including the levels of dopamine (DA) receptors, GSK3, and PSD95 as well as the dendrites and spines of medium spiny neurons (MSNs) and density of parvalbumin (PV) neurons [ 30 ]. Notably, the effects of these changes are somewhat counterbalanced, resulting in normal locomotor activity in Het Disc1 mice.…”

“…We therefore considered the Het Disc1 mice as a prodromal model of schizophrenia [ 30 ]. Environmental stressors might interact with the genetic defect of Disc1 haploinsufficiency and disrupt the counterbalanced condition of the altered DA system in Het Disc1 mice [ 30 ].…”