Elsevier

Schizophrenia Research

Volume 198, August 2018, Pages 60-67
Schizophrenia Research

Interaction of Brain-Derived Neurotrophic Factor Val66Met genotype and history of stress in regulation of prepulse inhibition in mice

https://doi.org/10.1016/j.schres.2017.08.019Get rights and content

Abstract

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism results in reduced activity-dependent BDNF release and has been implicated in schizophrenia. However, effects of the polymorphism on functional dopaminergic and N-methyl-d-aspartate (NMDA) receptor-associated activity remain unclear. We used prepulse inhibition, a measure of sensorimotor gating which is disrupted in schizophrenia, and assessed the effects of acute treatment with the dopamine receptor agonist, apomorphine (APO), and the NMDA receptor antagonist, MK-801. We used adult humanized hBDNFVal66Met ‘knockin’ mice which express either the Val/Val, Val/Met or Met/Met genotype. An interaction of BDNF with stress was modelled by chronic young-adult treatment with corticosterone (CORT). At 1 or 3 mg/kg, APO had no effect in Val/Val mice but significantly reduced PPI at the 100 ms inter-stimulus interval (ISI) in Val/Met and Met/Met mice. However, after CORT pretreatment, APO significantly reduced PPI in all genotypes similarly. At 0.1 or 0.25 mg/kg, MK-801 significantly disrupted PPI at the 100 ms ISI independent of genotype or CORT pretreatment. There were differential effects of APO and MK-801 on PPI at the 30 ms ISI and startle between the genotypes, irrespective of CORT pretreatment. These results show that the BDNF Val66Met Val/Met and Met/Met genotypes are more sensitive than the Val/Val genotype to the effect of APO on PPI. A history of stress, here modelled by chronic CORT administration, increases effects of APO in Val/Val mice.

Introduction

Brain-Derived Neurotrophic Factor (BDNF) is involved in brain development, synaptic function, neuroplasticity and cognition (Leal et al., 2014, Lu et al., 2014). Extensive research has implicated BDNF and its receptor, tropomyosin-related kinase B (TrkB), in the pathophysiology of a number of neuropsychiatric disorders (Castren, 2014, Notaras et al., 2015a, Notaras et al., 2015b) including schizophrenia (Buckley et al., 2007, Notaras et al., 2015a, Notaras et al., 2015b). Two lines of evidence particularly implicate BDNF as a mediator involved in schizophrenia development. Firstly, post-mortem studies on brains of patients with schizophrenia have found significantly reduced expression levels of BDNF and TrkB in prefrontal cortex or hippocampus (Weickert et al., 2003, Reinhart et al., 2015). These changes in expression are likely mediated by altered DNA Methylation of the BDNF gene, caused by environmental factors such as stress (Ikegame et al., 2013). Secondly, a common functional single nucleotide polymorphism in the BDNF gene has been associated with aspects of the illness. This polymorphism results in a Valine (Val) to Methionine (Met) substitution at codon 66 (Val66Met) and results in aberrant sorting and activity-dependent release of mature BDNF (Notaras et al., 2015a, Notaras et al., 2015b). While this BDNF polymorphism may not correlate to the incidence of schizophrenia per se, it is associated with clinical features such as age of onset, symptoms profile, aspects of brain morphology, neurocognitive functioning, and response to antipsychotic medication (for references, see Notaras et al., 2015a, Notaras et al., 2015b). However, it remains unclear how BDNF and the Val66Met polymorphism are involved in schizophrenia.

At a neurochemical level, BDNF has been shown to regulate dopaminergic activity (Guillin et al., 2007, Nikulina et al., 2014) and N-methyl-d-aspartate (NMDA) receptor function (Yamada and Nabeshima, 2004, Caldeira et al., 2007). For example, BDNF regulates dopamine D3 receptor expression (Sokoloff et al., 2002) and release and uptake dynamics of pre-synaptic dopamine transmission (Bosse et al., 2012), while in BDNF heterozygous mice exposed to chronic corticosterone treatment, NMDA NR2B subunits were markedly up-regulated (Klug et al., 2012). Subcortical dopaminergic hyperactivity and NMDA receptor hypofunction are widely implicated in schizophrenia and psychosis, as evidenced by numerous imaging and animal model studies (van den Buuse, 2010, Moghaddam and Javitt, 2012, Howes et al., 2017). However, little is known about the interaction of the BDNF Val66Met genetic variant with functional dopaminergic and NMDA receptor-mediated responses in behavioural models of schizophrenia. Here we used prepulse inhibition (PPI) of acoustic startle to investigate this relationship. We used a humanized Val66Met mouse model, in which part of the mouse BDNF gene has been replaced with a human sequence, containing either a Valine or Methionine (Cao et al., 2007), resulting in three genotypes: hBDNFVal/Val, hBDNFVal/Met or hBDNFMet/Met mice (Val/Val mice, Val/Met mice and Met/Met mice, respectively). We previously characterised the effects of chronic corticosterone (administered via the drinking water) on memory and baseline sensorimotor gating in these mice (Notaras et al., 2016, Notaras et al., 2017). In terms of sensorimotor gating, baseline prepulse inhibition (PPI) was slightly, though significantly reduced in Val/Met mice, but not Val/Val or Met/Met mice, particularly after chronic corticosterone treatment (Notaras et al., 2017). It remained unclear whether there were parallel BDNF Val66Met genotype differences in dopaminergic or NMDA receptor signalling, and whether chronic CORT treatment would affect these signalling mechanisms in a genotype-dependent manner. In the present study we therefore focused on dopaminergic and NMDA receptor-mediated regulation of PPI and compared mice with these three genotypes for their responses to acute treatment with the dopamine receptor agonist, apomorphine, and the NMDA receptor antagonist, MK-801. Both drugs have been extensively used in animal models to elicit PPI disruption similar to that observed in schizophrenia (Mansbach et al., 1988, Mansbach and Geyer, 1989, Geyer et al., 2001, van den Buuse, 2010). Similar to our previous studies (Notaras et al., 2016, Notaras et al., 2017), in late adolescence/young adulthood the animals were treated chronically with corticosterone (CORT), to simulate chronic stress. Because of known sex differences in the incidence and symptomatology of schizophrenia (Häfner, 2003), as well as numerous schizophrenia animal model studies (Wu et al., 2013, Hill, 2016), we included both male and female mice.

Section snippets

Animals

A total of 123 hBDNFVal66Met knockin mice on a C57Bl/6 background were obtained from a breeding colony at the La Trobe University Animal Research and Teaching Facility. This colony was established with breeders which were kindly provided by Prof. Joseph Gogos, Columbia University, New York, NY. Litters were obtained from Val/Met × Val/Met breeding pairs and housed on a 12:12 light cycle (lights on 7 a.m.) in individually-ventilated cages (IVC, Tecniplast, Italy) both during breeding and after

Effect of apomorphine (APO) on PPI and startle

As expected, analysis of PPI at the 100 ms ISI showed that treatment with APO significantly reduced PPI (main effect F(2,224) = 15.5, P < 0.001, Fig. 1) and this effect was most prominent at lower prepulse intensities (APO × PP interaction: F(6,672) = 6.14, P < 0.001, Table 2). The effect of APO was enhanced in mice pretreated with CORT (APO × CORT interaction: F(2,224) = 4.78, P = 0.009) and this effect was different between the genotypes in a prepulse intensity-dependent manner (APO × PP × genotype × CORT: F(12,672)

Discussion

The main result of this study was, that two doses of apomorphine that had no effect on PPI in BDNF Val66Met mice with the Val/Val genotype, significantly disrupted PPI in mice with the Val/Met and Met/Met genotype. Chronic CORT treatment several weeks before PPI testing, to simulate young-adult stress, had a lasting effect in Val/Val mice that now showed significantly reduced PPI after acute treatment with apomorphine. In Val/Met and Met/Met mice, CORT treatment did not significantly alter

Funding bodies

Author van den Buuse was supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia. Project funding was provided by the School of Psychology and Public Health at La Trobe University, Melbourne, Australia. None of these funding bodies had any influence on the design of the study, its execution, data analysis, or the writing of the manuscript.

Contributors

Authors Lee and Jaehne co-designed the study, performed all experimental procedures, and contributed to the first draft of the manuscript. Author Van den Buuse was the overall project leader and co-designed the study. He completed data analysis, prepared all figures, and wrote the final version of the manuscript.

Conflict of interest

None of the authors have any conflict of interest to disclose.

Acknowledgements

The authors are extremely grateful to Prof Joseph Gogos, Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, USA, for making available the original breeders from which our BDNF Val66Met breeding colony was established. We are also grateful to Dr Michael Notaras for critical discussion of the data.

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