Progress in Neuro-Psychopharmacology and Biological Psychiatry
Does genetic BDNF deficiency in rats interact with neurotransmitter control of prepulse inhibition? Implications for schizophrenia☆
Introduction
Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are involved in brain development, neuronal plasticity and neuron survival (Huang and Reichardt, 2001, Lu and Chow, 1999, McAllister et al., 1999). Several studies have suggested a role of BDNF in the development of schizophrenia. These studies include post-mortem analysis which revealed significant reduction of BDNF transcripts (Reinhart et al., 2015, Thompson Ray et al., 2011, Wong et al., 2010) or protein expression (Hashimoto et al., 2005, Issa et al., 2010, Rao et al., 2015, Weickert et al., 2003) in brain regions implicated in schizophrenia. These reductions were also found in plasma (Green et al., 2011, Yoshimura et al., 2016) and may be mediated by altered epigenetic control of BDNF expression (Mitchelmore and Gede, 2014, Ursini et al., 2016). A common single-nucleotide polymorphism in the BDNF gene, the val66met polymorphism, has been implicated in aspects of schizophrenia (for references, see (Notaras et al., 2015b)). However, the exact role of BDNF in schizophrenia symptoms remains unclear.
Animal models of reduced BDNF signalling have been used to investigate the effect of such reduction on schizophrenia endophenotypes. Animal models allow close control of experimental variables such as genetic variability (background) and environmental factors. For example, we previously used mice heterozygous for a targeted mutation in the BDNF gene and investigated the effect of chronic treatment with corticosterone, to simulate chronic stress. This ‘two-hit’ gene-environment approach revealed significant impairment of short-term spatial memory in the Y-maze (Klug et al., 2012) and differential effects of glutamatergic (Klug et al., 2012), dopaminergic and serotonergic drugs on prepulse inhibition (PPI), an operational measure of sensorimotor gating, which is disrupted in schizophrenia. PPI has been widely used to study the interaction of brain circuitry and genes putatively involved in schizophrenia (van den Buuse, 2010). The combination of BDNF heterozygosity and corticosterone treatment in mice resulted in marked up-regulation of the NR-2B subunit of the N-methyl-d-aspartate (NMDA) receptor (Klug et al., 2012) which plays an important role in both memory (Morris, 2013) and PPI regulation (Geyer et al., 2001, van den Buuse, 2010) and has been implicated in schizophrenia in numerous studies (Gilmour et al., 2012). Altered NMDA receptor activity has been widely implicated in schizophrenia (Howes et al., 2015, Javitt, 2007) and BDNF has been widely implicated in development and plasticity of glutamatergic synapses (Carvalho et al., 2008, Gottmann et al., 2009). Further ‘two-hit’ studies in BDNF heterozygous mice, including drugs of abuse such as cannabinoids and methamphetamine, similarly showed altered NMDA receptor-mediated control of PPI, as well as reduced baseline PPI (Klug and van den Buuse, 2013, Manning and van den Buuse, 2013).
In the present study we aimed to further investigate the role of BDNF in PPI regulation. Here we used BDNF heterozygous mutant rats (BDNF HET rats), which express BDNF levels approximately 50% of those observed in wildtype controls (Gururajan et al., 2015). As compared to mice, rats display a richer behavioural repertoire and perform better on complex cognitive and operant tasks of relevance to human cognition (Parker et al., 2014). The pharmacological regulation of PPI, including NMDA receptors, has been studied extensively in rats (Geyer et al., 2001, Koch and Schnitzler, 1997, van den Buuse, 2010), however there is limited information on BDNF mutant rats. We previously used BDNF HET rats in a gene-environment study and observed a tendency for PPI to be lower in these animals when compared to wildtype controls (Gururajan et al., 2015). However, the decrease of PPI induced by treatment with the dopamine receptor agonist, apomorphine, was unaltered in BDNF HET rats compared to controls, suggesting normal dopaminergic control of PPI in these animals. Moreover, there were no interactive effects of simulated stress, in the form of chronic corticosterone treatment, in this species (Gururajan et al., 2015). In light of the role of NMDA receptors in schizophrenia and PPI regulation, the aim of the present study was to extend these previous observations and to investigate whether there are differential effects of the NMDA receptor antagonist, MK-801, on PPI and startle in BDNF HET rats and WT controls. For comparison, we also assessed the effect of drugs affecting the serotonin system, in particular the serotonin-1A receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), the serotonin-2A receptor agonist, DOI, and the serotonin releaser, fenfluramine (Geyer et al., 2001, van den Buuse, 2010).
NMDA receptor-mediated control of PPI can be modulated by other glutamate receptors. Most notably, it has been shown that activation of mGluR2/3 receptors is able to reverse the effect of NMDA receptor antagonists, such as MK-801 and ketamine (Hikichi et al., 2013, Imre et al., 2006), whereas blockade of mGluR5 has been shown to enhance the effect of such drugs (Campbell et al., 2004, Henry et al., 2003). To assess whether genetic BDNF deficiency would alter the interaction between NMDA receptor-mediated PPI disruption and metabotropic glutamate receptor modulation, in addition to the effect of MK-801 on PPI on its own, we therefore also studied its action in combination with that of the mGluR2/3 receptor agonist, LY379,268, or the mGluR5 receptor antagonist, 2-Methyl-6-(phenylethynyl)pyridine (MPEP).
Section snippets
Animals
This study used BDNF heterozygous mutant rats and their wildtype littermate controls. The breeding colony and stock animals were kept in individually-ventilated cages (IVC, Tecniplast, Italy) under standard vivarium conditions including a 12:12 h light cycle (lights on at 7:00 am) and unlimited supply of standard pellet food. The rats were weaned at 3–4 weeks of age and used for experimentation when they were 12–20 weeks of age. Two cohorts were used for the MK-801 and serotonin studies,
MK-801 dose-response
We examined the effect of 0.02, 0.05 and 0.1 mg/kg of MK-801 to assess whether BDNF HET rats showed differential changes in PPI and startle when compared to WT controls. Across the different MK-801 doses, PPI in BDNF HET rats was significantly lower than in WT rats (F(1,111) = 4.5, P = 0.035) (Fig. 1). Administration of MK-801 caused a dose-dependent decrease in PPI (main effect of Drug: F(3,111) = 24.7, P < 0.001) which was not statistically different between WT and BDNF HET rats (no Drug × Genotype
Discussion
The aim of this study was to investigate the relationship between reduced levels of BDNF in the brain and the regulation of PPI, an endophenotype of schizophrenia. We used BDNF HET mutant rats in which we previously found an approximately 50% decrease of mature BDNF protein levels, at least in the dorsal hippocampus (Gururajan et al., 2014, 2015). Based on the widely accepted hypoglutamatergia in schizophrenia (Howes et al., 2015, Javitt, 2007), we focused on the effects of the NMDA receptor
Acknowledgements
This study was supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia (1041895). This organization had no role in the study design, the collection, analysis and interpretation of the data, the writing of this report, or the decision to submit the article for publication. The authors have no actual or potential conflicts of interest to disclose.
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