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. 2014 Apr;3(3):202-211.
doi: 10.4236/ojmp.2014.33022.

Hypo-anxious phenotype of adolescent offspring prenatally exposed to LPS is associated with reduced mGluR5 expression in hippocampus

Dany Arsenault  1 , Aijun Zhu  1 , Chunyu Gong  1 , Kun-Eek Kil  1 , Sreekanth Kura  1 , Ji-Kyung Choi  1 , Anna-Liisa Brownell  1
Affiliations

Hypo-anxious phenotype of adolescent offspring prenatally exposed to LPS is associated with reduced mGluR5 expression in hippocampus

Dany Arsenault et al. Open J Med Psychol. 2014 Apr.

Abstract

Many studies have reported long-term modulation of metabotropic glutamate receptor 5 (mGluR5) by inflammatory processes and a pharmacological modulation of mGluR5 is known to regulate anxiety level. However, it is not known if non-pharmacological modulation of mGluR5 by inflammation impaired the unconditional level of anxiety. In this study, we investigated this relation in LPS prenatal immune challenge (120μg/kg, 3x i.p. injection in late gestation), a developmental model of neuroinflammation in which some studies have reported hypo-anxious phenotype. Using positron emission tomographic imaging (PET) approaches, we have demonstrated a decrease in the binding potential of [18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB, a radioligand for mGluR5) in hippocampus of adolescent offspring prenatally exposed to LPS, without significant change in the binding of [11C]peripheral benzodiazepine receptor 28 ([11C]PBR28), an inflammatory marker. In addition, dark-light box emergence test revealed a lower level of anxiety in LPS-exposed offspring and this behavioural phenotype was associated with the binding potential of [18F]FPEB in hippocampus. These results confirm that neuroinflammation during developmental phase modulates the physiology of mGluR5 and this alteration can be associated with behavioural phenotype related to anxiety. In addition, this study supports a hypotheses that mGluR5 could be used as a diagnostic target in anxiety.

Keywords: Behavior; anxiety; immune response; inflammation; mGluR5.

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Figures

Figure 1
Figure 1
Time line of experimentations. Pregnant mice (C57BL/6) received daily injections of 120 μg/kg of LPS or an equivalent volumes of saline from GD15 to GD17. Motor function was measured by grasping test between PnD29 and PnD30 whereas dark-light box emergence test was used to quantify the unconditioned anxiety level (between PnD33 and PnD35). Two imaging sessions were performed to evaluate the in vivo expression of mGluR5 (PnD37-PnD39) and PBR (PnD42-PnD44). Abbreviations: GD, gestational day; [11C]PBR28, peripheral benzodiazepine receptor 28; [18F]FPEB, [18F]fluoro-5-(2-pyridinylethynyl)benzonitrile; PnD, postnatal day.
Figure 2
Figure 2
LPS prenatal treatment does not change the binding level of brain [11C]PBR. (A) whole brain imaging of [11C]PBR28 .... or coronal slice of brain imaging showing that .... (B) PET imaging using [11C]PBR28 targeting activated microglia did not show significant difference between various brain structures. Values are expressed as mean ± SEM. Statistical analyses were performed using two-way analysis of variance (ANOVA). The number of males and females was 11–13 and 13–16 for saline group, whereas it was 15–17 and 9–13 for LPS group. Abbreviations: CTX, cortex; CRBL, cerebellum; F-LPS, female-LPS; F-Sal, female-saline; HC, hippocampus; HTH, hypothalamus; M-Sal, male-saline; M-LPS, male-LPS; OB, olfactory bulb; S, striatum; W, whole brain.
Figure 3
Figure 3
Decrease binding potential of [18F]FPEB in hippocampus of LPS-exposed offspring. (A) whole brain imaging of mGluR5 .... or coronal slice of brain imaging showing that .... (B) PET imaging revealed a decreased binding potential of [18F]FPEB in hippocampus of both males and females prenatally exposed to LPS, without significant changes in other brain structures. Values are expressed as mean ± SEM. Statistical analyses were performed using two-way analysis of variance (ANOVA). The number of males and females was 14–17 and 10–11 for saline group, whereas it was 13–15 and 14–16 for LPS group. Abbreviations: CTX, cortex; F-LPS, female-LPS; F-Sal, female-saline; HC, hippocampus; HTH, hypothalamus; M-Sal, male-saline; M- LPS, male-LPS; OB, olfactory bulb; S, striatum; W, whole brain. * P < 0.05
Figure 4
Figure 4
Reduction of unconditioned anxiety level in adolescent offspring prenatally exposed to LPS. (A) LPS prenatal exposition did not change the weight of offspring at PnD30. (B) Dark-light box test showed that both males and females exposed to LPS spent more time in the light compartment. (C) Further analysis showed that the number of box alteration did not significantly change in LPS-treated offspring. However, LPS-exposed offspring spent more time per exploratory event in the light box. (D) Grasping ability was similar between all groups. (E) The binding level of [18F]FPEB in hippocampus correlated negatively with the time spent in the light box. Values are expressed as mean ± SEM. Statistical analyses were performed using two-way analysis of variance (ANOVA). Correlation was determined by linear regression analysis. Each dot represents a single animal. For panel A to D, the number of males and females was 25–29 and 22–23 for saline group, whereas it was 20 and 19–20 for LPS group. Abbreviations: M-Sal, male-saline; F-Sal, female-saline; M-LPS, male-LPS; F-LPS, female-LPS. * P < 0.05; ** P < 0.01
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