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. 2019 Apr 9:10:222.
doi: 10.3389/fpsyt.2019.00222. eCollection 2019.

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

Taygun C Uzuneser  1 , Jil Speidel  1 , Georgios Kogias  1 , An-Li Wang  2 , Maria A de Souza Silva  2 , Joseph P Huston  2 , Iulia Zoicas  1 , Stephan von Hörsten  3 , Johannes Kornhuber  1 , Carsten Korth  4 , Christian P Müller  1
Affiliations

Disrupted-in-Schizophrenia 1 (DISC1) Overexpression and Juvenile Immune Activation Cause Sex-Specific Schizophrenia-Related Psychopathology in Rats

Taygun C Uzuneser et al. Front Psychiatry. .

Abstract

Synaptic pruning is a critical refinement step during neurodevelopment, and schizophrenia has been associated with overpruning of cortical dendritic spines. Both human studies and animal models implicate disrupted-in-schizophrenia 1 (DISC1) gene as a strong susceptibility factor for schizophrenia. Accumulating evidence supports the involvement of DISC1 protein in the modulation of synaptic elimination during critical periods of neurodevelopment and of dopamine D2-receptor-mediated signaling during adulthood. In many species, synaptic pruning occurs during juvenile and adolescent periods and is mediated by microglia, which can be over-activated by an immune challenge, giving rise to overpruning. Therefore, we sought to investigate possible interactions between a transgenic DISC1 model (tgDISC1) and juvenile immune activation (JIA) by the bacterial cell wall endotoxin lipopolysaccharide on the induction of schizophrenia-related behavioral and neurochemical disruptions in adult female and male rats. We examined possible behavioral aberrations along three major symptom dimensions of schizophrenia including psychosis, social and emotional disruptions, and cognitive impairments. We detected significant gene-environment interactions in the amphetamine-induced locomotion in female animals and in the amphetamine-induced anxiety in male animals. Surprisingly, gene-environment interactions improved social memory in both male and female animals. JIA alone disrupted spatial memory and recognition memory, but only in male animals. DISC1 overexpression alone induced an improvement in sensorimotor gating, but only in female animals. Our neurochemical analyses detected sex- and manipulation-dependent changes in the postmortem monoamine content of animals. Taken together, we here report sex-specific effects of environment and genotype as well as their interaction on behavioral phenotypes and neurochemical profiles relevant for schizophrenia.

Keywords: animal model; disrupted-in-schizophrenia 1; gene environment interaction; immune activation; schizophrenia; synaptic pruning.

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Figures

Figure 1
Figure 1
Graphical depiction of the sequence of manipulations and behavioral tests. Animals were genotyped 2 weeks after birth to assess the presence or absence of the knocked-in human DISC1 transgene. Male and female animals without the transgene (wild type) and with the transgene on both alleles (homozygous tgDISC1) were used for behavioral and neurochemical experiments. A day after weaning, animals started receiving LPS or SAL injections (i.p). on alternate days (days 22, 24, 26, 28, and 30). When animals reached adulthood (day 63), behavioral testing began. Animals were tested for SD (day 63), NOR (day 65), SNP (day 67), amphetamine-induced locomotion (day 69), and PPI (day 71). Animals were later sacrificed, and their brains were collected for neurochemical analyses. LPS, lipopolysaccharide; SD, social discrimination; NOR, novel object recognition; SNP, spatial novelty preference; OF, open field; PPI, prepulse inhibition; PND, postnatal day.
Figure 2
Figure 2
The effects of tgDISC1 with or without juvenile LPS administration on baseline and amphetamine-induced locomotor activity in adult female (left) and male rats (right). Baseline and amphetamine-induced locomotion are shown as activity at single time points for female (A) and male rats (C). Baseline and amphetamine-induced locomotion are shown as overall activity for female (B) and male rats (D). Arrow represents the amphetamine injection time, which is set to min 0. n = 6–10 per group. Amphetamine challenge dose = 1.5 mg/kg. Values are shown as mean ± SEM. *p < 0.05, **p < 0.01 compared to WT/VEH. WT, wild type; VEH, vehicle; LPS, lipopolysaccharide; AMPH, amphetamine; AUC, area under the curve.
Figure 3
Figure 3
The effects of tgDISC1 with or without juvenile LPS administration on three different aspects of memory performance in adult female (left) and male rats (right). Spatial memory performance, which was tested using a Y-maze, is shown using the parameters of arm duration and arm visit for female (A and B) and male rats (C and D). Recognition memory performance and object exploration time are shown for female (E and F) and male rats (G and H). Social memory performance and social preference are shown for female (I and J) and male rats (K and L). n = 6–10 per group. Values are shown as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared to WT/VEH. WT, wild type; VEH, vehicle; LPS, lipopolysaccharide.
Figure 4
Figure 4
The effects of tgDISC1 with or without juvenile LPS administration on baseline and amphetamine-induced center behavior in the OF as a measure of anxiety in adult female (left) and male rats (right). Baseline and amphetamine-induced center time and center locomotion ratio are shown for female (A and B) and male rats (C and D). n = 6–10 per group. Amphetamine challenge dose = 1.5 mg/kg. Values are shown as mean ± SEM. *p < 0.05, **p < 0.01 compared to WT/VEH. WT, wild type; VEH, vehicle; LPS, lipopolysaccharide; AMPH, amphetamine; AUC, area under the curve.
Figure 5
Figure 5
The effects of tgDISC1 with or without juvenile LPS administration on sensorimotor gating in adult female (left) and male rats (right). Prepulse inhibition of the acoustic startle stimulus is shown for each prepulse–pulse pair for female (A) and male rats (C). Prepulse inhibition of the acoustic startle stimulus is shown as the overall inhibition for female (B) and male rats (D). Background noise = 68 dB. n = 6–10 per group. Values are shown as mean ± SEM. *p < 0.05, **p < 0.01 compared to WT/VEH. WT, wild type; VEH, vehicle; LPS, lipopolysaccharide; PPI, prepulse inhibition; P100, pulse intensity = 100 dB; P110, pulse intensity = 110 dB; P120, pulse intensity = 120 dB.
Figure 6
Figure 6
The effects of tgDISC1 with or without juvenile LPS administration on postmortem monoamine levels in adult female rats. Postmortem tissue levels of dopamine (A, D, and G), serotonin (B, E, and H), and noradrenaline (C, F, and I) are shown for ventral striatum, dorsal striatum, and prefrontal cortex, respectively. n = 6–10 per group. Values are shown as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared to WT/VEH. WT, wild type; VEH, vehicle; LPS, lipopolysaccharide.
Figure 7
Figure 7
The effects of tgDISC1 with or without juvenile LPS administration on postmortem monoamine levels in adult male rats. Postmortem tissue levels of dopamine (A, D, and G), serotonin (B, E, and H), and noradrenaline (C, F, and I) are shown for ventral striatum, dorsal striatum, and prefrontal cortex, respectively. n = 7–10 per group. Values are shown as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 compared to WT/VEH. WT, wild type; VEH, vehicle; LPS, lipopolysaccharide.
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