Does genetic BDNF deficiency in rats interact with neurotransmitter control of prepulse inhibition? Implications for schizophrenia

https://doi.org/10.1016/j.pnpbp.2017.02.009Get rights and content

Highlights

  • Prepulse inhibition (PPI) and brain BDNF levels are reduced in schizophrenia.

  • Decreased BDNF levels in BDNF heterozygous (HET) rats compared to wildtype controls

  • No genotype effect on PPI at baseline or effect of NMDA receptor antagonist MK-801.

  • No differences in serotonergic regulation of PPI between the genotypes.

  • Genetic BDNF deficiency does not lead to altered regulation of PPI.

Abstract

Several studies have suggested a role of BDNF in the development of schizophrenia. For example, post-mortem studies have shown significantly reduced levels of BDNF protein expression in the brain of schizophrenia patients. We investigated the relationship between reduced levels of BDNF in the brain and the regulation of prepulse inhibition (PPI), a behavioral endophenotype of schizophrenia. We used BDNF heterozygous mutant rats which display a 50% decrease of mature BDNF protein levels. Previously, we observed normal baseline PPI and responses to the dopamine D1/D2 receptor agonist, apomorphine, in these rats. Here, we focused on the effects of the NMDA receptor antagonist, MK-801, its interaction with mGluR2/3 and mGluR5 receptors, and the PPI response to serotonergic drugs.

MK-801 administration caused a dose-dependent reduction of PPI and increase of startle amplitudes. Baseline PPI and the effect of 0.02–0.1 mg/kg of MK-801 were not significantly altered in male or female BDNF heterozygous rats, although the MK-801-induced increase in startle levels was reduced. Co-treatment with the mGluR2/3 agonist, LY379,268, or the mGluR5 antagonist, MPEP, did not alter the effect of MK-801 on PPI in controls or BDNF mutant rats. Treatment with the serotonin-1A receptor agonist, 8-OH-DPAT, the serotonin-2A receptor agonist, DOI, or the serotonin releaser, fenfluramine, induced differential effects on PPI and startle but these effects were not different between the genotypes.

These results show that a significant decrease of BDNF protein expression does not lead to reduced PPI at baseline or changes in the regulation of PPI via NMDA receptors or serotonergic mechanisms. These findings in a genetic rat model of BDNF deficiency do not support a role for similar reductions of BDNF levels in schizophrenia in the disruption of PPI, widely reported as an endophenotype of the illness. The potential implications of these results for our understanding of changes in PPI and BDNF expression in schizophrenia are discussed.

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.

References (55)

  • D.C. Javitt

    Glutamate and schizophrenia: phencyclidine, N-methyl-d-aspartate receptors, and dopamine-glutamate interactions

    Int. Rev. Neurobiol.

    (2007)
  • M. Klug et al.

    Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice

    Neurobiol. Dis.

    (2012)
  • M. Koch et al.

    The acoustic startle response in rats - circuits mediating evocation, inhibition and potentiation

    Behav. Brain Res.

    (1997)
  • J.A. Larrauri et al.

    Differential effects of the antidepressant mirtazapine on amphetamine- and dizocilpine-induced PPI deficits

    Pharmacol. Biochem. Behav.

    (2012)
  • T. Laudes et al.

    Impaired transmission at corticothalamic excitatory inputs and intrathalamic GABAergic synapses in the ventrobasal thalamus of heterozygous BDNF knockout mice

    Neuroscience

    (2012)
  • J.S. Lindholm et al.

    The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf(+)/(−) heterozygous null mice

    Neuropharmacology

    (2012)
  • C. Mitchelmore et al.

    Brain Derived Neurotrophic Factor: epigenetic regulation in psychiatric disorders

    Brain Res.

    (2014)
  • R.G. Morris

    NMDA receptors and memory encoding

    Neuropharmacology

    (2013)
  • M. Notaras et al.

    A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review

    Neurosci. Biobehav. Rev.

    (2015)
  • C.C. Parker et al.

    Rats are the smart choice: rationale for a renewed focus on rats in behavioral genetics

    Neuropharmacology

    (2014)
  • N. Pitsikas et al.

    The metabotropic glutamate 2/3 receptor agonist LY379268 counteracted ketamine-and apomorphine-induced performance deficits in the object recognition task, but not object location task, in rats

    Neuropharmacology

    (2014)
  • V. Reinhart et al.

    Evaluation of TrkB and BDNF transcripts in prefrontal cortex, hippocampus, and striatum from subjects with schizophrenia, bipolar disorder, and major depressive disorder

    Neurobiol. Dis.

    (2015)
  • J. Wong et al.

    Promoter specific alterations of brain-derived neurotrophic factor mRNA in schizophrenia

    Neuroscience

    (2010)
  • I. Abidin et al.

    Reduced presynaptic efficiency of excitatory synaptic transmission impairs LTP in the visual cortex of BDNF-heterozygous mice

    Eur. J. Neurosci.

    (2006)
  • S.A. Brody et al.

    Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors

    Mol. Psychiatry

    (2004)
  • U.C. Campbell et al.

    The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates PCP-induced cognitive deficits in rats

    Psychopharmacology (Berl)

    (2004)
  • A.L. Carvalho et al.

    Role of the brain-derived neurotrophic factor at glutamatergic synapses

    Br. J. Pharmacol.

    (2008)
  • Cited by (0)

    Progress in neuropsychopharmacology and biological psychiatry.

    View full text