The effect of 17β-estradiol on maternal immune activation-induced changes in prepulse inhibition and dopamine receptor and transporter binding in female rats
Introduction
Neurodevelopmental models of schizophrenia are based on epidemiological evidence that exposure to adverse events during the pre- or perinatal period increases the risk of developing the illness (Brown and Derkits, 2010). The maternal immune activation (MIA) animal model involves prenatal exposure to infection, which instigates significant inflammatory processes in the foetal brain during a period of critical development (Meyer et al., 2006). In rodents, evidence suggests that exposure to infection during gestation results in schizophrenia-like behaviours in adulthood; in particular the polyinosinic–polycytidylic acid (poly(I:C)) model is increasingly being used due to its capacity to account for several aspects of schizophrenia epidemiology, pathophysiology and symptomatology (Meyer and Feldon, 2012). Inflammation can be artificially induced by treatment with poly(I:C), a synthetic analogue of double-stranded RNA that mimics the acute phase of the response to a viral infection (Kimura et al., 1994). Administration of poly(I:C) to a pregnant dam causes an increase in levels of pro-inflammatory cytokines including interleukin-1β, interleukin-6 and tumour necrosis factor-α (Cunningham et al., 2007) by activating the transmembrane protein toll-like receptor 3 (Akira and Takeda, 2004). Consequently, typical neurodevelopment in poly(I:C) offspring is impaired. For example, dam exposure to poly(I:C) resulted in enlarged ventricles and reduced hippocampal size in the offspring, similar to that seen in schizophrenia patients (Piontkewitz et al., 2009). Offspring also exhibit enhanced psychosis-like behaviour, cognitive impairment and neurochemical changes relevant to those observed in schizophrenia (Duchatel et al., 2019; Gogos et al., 2020; Gray et al., 2019; Howland et al., 2012; Luchicchi et al., 2016; Meehan et al., 2017; Osborne et al., 2019; Piontkewitz et al., 2011; Purves-Tyson et al., 2019; Rahman et al., 2017; Wolff and Bilkey, 2010; Zuckerman et al., 2003).
Several studies have shown that intravenous administration of poly(I:C) in rats during mid-late gestation (i.e. gestation day 15, equivalent to the second trimester in humans) is most effective in producing adult offspring with disruption of baseline prepulse inhibition (PPI) (Ballendine et al., 2015; Bikovsky et al., 2016; Gogos et al., 2020; Howland et al., 2012; Luchicchi et al., 2016; Wolff and Bilkey, 2008, Wolff and Bilkey, 2010; Yee et al., 2011). To date, no studies have examined dopaminergic regulation of PPI in rat poly(I:C) offspring. Further, while the majority of studies were conducted in male rats, we and others have examined sex differences and reported similar PPI disruption in male and female poly(I:C) offspring (Gogos et al., 2020; Howland et al., 2012; Zuckerman et al., 2003). It is suggested that aberrant dopaminergic neurotransmission may underlie some of the behavioural deficits observed in poly(I:C) offspring. One study administering poly(I:C) on gestation day 15 showed increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex, of poly(I:C)-treated rat offspring (Luchicchi et al., 2016). In the nucleus accumbens, rats and mice treated with poly(I:C) in early gestation (day 9/10) showed increased dopamine D1 receptor levels (Meehan et al., 2017; Vuillermot et al., 2010), while mice also showed increased dopamine D2 receptor expression in adulthood and reduced dopamine transporter expression in adolescence (Vuillermot et al., 2010). In the current study, we will examine whether behavioural deficits in female poly(I:C) rat offspring correspond to changes in dopamine neurotransmission, specifically dopamine receptor and transporter binding density.
Clinical and preclinical evidence demonstrates that the sex steroid hormone, 17β-estradiol, has therapeutic potential for schizophrenia (Gogos et al., 2019; Gogos et al., 2015; Kulkarni et al., 2015; Sbisa et al., 2017). For example, a large-scale randomised-controlled trial in premenopausal women with treatment-resistant schizophrenia found that treatment with estradiol reduced positive, general and total symptoms (as assessed using the Positive and Negative Syndrome Scale) compared to placebo treatment (Kulkarni et al., 2015). We showed in ovariectomised female rats, that treatment with the estrogenic compounds, 17β-estradiol, raloxifene and tamoxifen, attenuated acute dopamine-mediated reduced PPI (Gogos and van den Buuse, 2015; Sbisa et al., 2018). In a study measuring dopamine and serotonin receptors/transporters, we found that 17β-estradiol treatment altered central indices of dopaminergic, but not serotonergic function (Chavez et al., 2010). Specifically, in the nucleus accumbens, ovariectomised rats had reduced dopamine transporter and increased dopamine D2 receptor density; 17β-estradiol treatment reversed these changes (Chavez et al., 2010). To the best of our knowledge, the effects of 17β-estradiol on behaviour have not been tested in rat poly(I:C) offspring. Moreover, here we assess the effects of 17β-estradiol treatment in intact, rather than ovariectomised rats, providing a model that is clinically relevant to premenopausal women.
Thus, the aim of the current study was to explore the modulatory effect of 17β-estradiol on psychosis-like PPI deficits in the rat poly(I:C) model of schizophrenia. Our prediction was that poly(I:C) offspring would show disruption of PPI and that this endophenotype of schizophrenia would be reversed by chronic treatment with 17β-estradiol. We also aimed to determine whether the effects of 17β-estradiol and poly(I:C) on behaviour were associated with changes in dopaminergic activity. While no other study has examined these dopaminergic indices in the GD15 poly(I:C) rat model, we predicted a poly(I:C)-induced increase in dopamine D1 and D2 receptor levels in the nucleus accumbens (Meehan et al., 2017; Vuillermot et al., 2010), but not the frontal cortex (Luchicchi et al., 2016), and that 17β-estradiol treatment would reverse this (Chavez et al., 2010). These aims were addressed in two ways: we examined the effect of dopaminergic drugs on PPI and we used autoradiography to measure dopamine receptor and transporter binding density.
Section snippets
Animals
32 outbred Long Evans (LE) rats (24 dams and 8 studs) were obtained from a breeding colony at the Florey Institute of Neuroscience and Mental Health (VIC, Australia) or the Australian Resource Centre (WA, Australia). These rats were used to generate the 38 female offspring that were later tested for behavioural changes and radioligand binding. All rat breeding, treatments and behavioural testing were carried out in the Behavioural Neuroscience suites at the La Trobe Animal Research and Teaching
Offspring body and uterus weight
Analysis of offspring body weight on the day of implant surgery, or at the end of the experiment found no significant main effect of condition, treatment, or an interaction of these (Table 1). However, analysis of body weight gain throughout the experiment showed a significant effect of treatment (day × treatment interaction: F1, 34 = 4.30, P = 0.046, partial η2 = 0.11), reflecting a slightly greater weight gain in 17β-estradiol-treated offspring. There was no main effect of condition,
Discussion
The current study aimed to explore the effects of 17β-estradiol treatment on MIA-induced behavioural and neurochemical changes in female rat poly(I:C) offspring. Key findings included that 17β-estradiol treatment reversed a schizophrenia-like PPI deficit in poly(I:C) offspring. We also observed differential changes in the acute effects of methamphetamine and apomorphine in control offspring vs. poly(I:C) offspring, suggesting altered dopaminergic regulation of PPI. This was confirmed by
Contributors
AS and DZ conducted the experiments; AG, MvdB and SK designed the study and supervised data collection; AG and MvdB funded the study and conducted data analysis; all authors contributed to drafting the manuscript.
Role of the funding source
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Data statement
Data will be available upon request. Contact Andrea Gogos: [email protected].
Declaration of competing interest
There are no conflicts of interest to report.
Acknowledgements
AG is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia (ID 1108098). The authors gratefully acknowledge the financial support of the Jared Purton Foundation and the One-in-Five Foundation. The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government's Operational Infrastructure Support Grant.
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