Research reportBrain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid lesions of the ventral hippocampus
Introduction
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, was first isolated from pig brain in 1982 [4] and was subsequently cloned and characterized in the rat and the human [20], [26]. In the hippocampus, cortex and in vitro, BDNF has been demonstrated to regulate the survival, differentiation, morphology and synaptic remodeling of neurons [2], [13], [15], [18], [27], [37]. It has also been demonstrated to modulate neurotransmitter synthesis, metabolism and release, postsynaptic ion channel fluxes, neuronal activity and long term potentiation [3], [7], [16], [37]. The association of BDNF with neurodevelopment, cell viability and synaptic strength make it an attractive candidate for involvement in schizophrenia. This claim is based on the evidence supporting abnormal neurodevelopment as a predisposing factor in the development of schizophrenia [41] in combination with growing evidence that a neurodegenerative component is also present in schizophrenia [9]. Support for a role for BDNF in schizophrenia also stems from the demonstration that it is decreased by factors correlated with first episode onset such as stress [35], [36] and estrogen withdrawal [34]. In addition, stress induced decreases in BDNF are blocked by 5-HT2 receptor antagonists, a receptor binding property of many neuroleptics [39]. Electroconvulsive treatment (ECT), effective in treatment-resistant schizophrenia in combination with neuroleptics [32], also upregulates the expression of BDNF [23], [30]. These findings lead to the inference that BDNF may be altered in schizophrenia. Direct investigations of BDNF in schizophrenia also suggest it may be altered. Findings indicate that hippocampal BDNF mRNA is reduced [5] as is serum BDNF in schizophrenic patients [38]. An allele variant of the BDNF gene has also been identified in a population of schizophrenic patients [40]. These factors suggest that disruptions of BDNF may play a role in the etiology of this disorder by compromising neuroplasticity or altering neurotransmission.
The animal model established by Lipska et al. [25] was used to test the hypothesis that neurodevelopmental abnormalities modeling schizophrenia create a functionally compromised system with alterations in factors necessary for maintaining neuron viability and neuronal communication. The overall result would be a system more susceptible to neuronal atrophy and/or death caused by environmental factors such as stress.
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Animals
Timed pregnant Sprague–Dawley rats were obtained from Charles River Canada (Montreal, Quebec, Canada) at 14 days gestation. All animals were housed in clear plastic cages at a room temperature of 19–21 °C on a 12-h light/dark cycle. Animals were allowed access to food and water ad libitum. All procedures involving animals were done in accordance with the guidelines of the Canadian Council on Animal Care and were approved by the University of Saskatchewan Committee of Animal Care and Supply.
Surgery
Histological analysis
Sections through the ventral hippocampus of lesion and sham rats, stained with haematoxylin and eosin were assessed for animal inclusion or exclusion. Rats infused with ACSF that were included in the study demonstrated no observable cell loss in or around the ventral hippocampus (see Fig. 1). Of the total number of animals infused with ACSF, approximately 70% were included in further experiments. Animals excluded generally showed small rims of unilateral or bilateral cell loss in the CA3
BDNF mRNA in the prefrontal cortex
The results of the present study demonstrate that basal BDNF mRNA levels are reduced in the prefrontal cortex of rats with neonatal ibotenic acid lesions of the ventral hippocampus. Reductions in baseline BDNF mRNA expression could result in alterations in neuronal morphology, specifically dendritic atrophy [27], as well as reduced synaptic plasticity [37] and reduced neuronal survival [13]. The inter-relationship between BDNF and the neurotransmitters GABA and glutamate also suggests that
Conclusions
The present study demonstrates a reduction in basal BDNF mRNA levels in the prefrontal cortex and the hippocampal formation of animals with neonatal ibotenic acid lesions of the hippocampus. Reductions in basal BDNF levels could result in alterations in neuronal connectivity by producing a situation of increased neuronal atrophy and fewer synapses. Alterations in synaptic density have not been investigated in the model, however, the reduction in BDNF mRNA would suggest that this may occur. As
Uncited references
[10]; [14]
Acknowledgements
The authors wish to thank Saskatchewan Health and the Schizophrenia Society of Saskatchewan for their support. This work was part of a Ph.D. thesis completed by Paula C. Ashe at the University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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2022, NeuroscienceCitation Excerpt :For example, rats prenatally exposed to the antiproliferative agent MAM (Methylazoxymethanol) manifested behavioral deficits and significant decreases of BDNF in the hippocampus (Fiore et al., 2002). Interestingly, Ashe et al. (2002) and Lipska et al. (2001) both showed a significant reduction of BDNF mRNA in the prefrontal cortex and hippocampus of animals that received neonatal lesions of the ventral hippocampus. In human studies, decreased BDNF concentrations in cortical and hippocampal areas of schizophrenic patients have been documented (Durany et al., 2001).
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2013, Drug and Alcohol DependenceCitation Excerpt :Differential forms of hippocampal network failure (e.g., potentially spanning different forms of dual diagnosis disorders in humans) appear to produce similar secondary effects on prefrontal cortical–striatal network function underpinning impulsive behavior, augmentation of DA-mediated striatal-based habit learning, and ultimately increased addiction vulnerability. For instance, NVHL rats show low expression patterns of brain-derived neurotrophic factor (BDNF) in hippocampal and cortical–striatal circuits (Ashe et al., 2002), indicative of low capacity for neuroplastic change, while cocaine exposure increases BDNF expression in the NAC, indicating pathological increases in neuroplasticity (Graham et al., 2007). Given that addictive drugs also augment dendritic complexity in striatal regions associated with habit formation (Robinson and Kolb, 2004), a state of low hippocampal functionally, often encompassing suppressed neurogenic activity, may prime conditions where the neuroplastic effects of addictive drugs more efficiently recruit striatal circuits leading to the habit formation of drug-seeking and taking.
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2012, Psychiatric Clinics of North AmericaCitation Excerpt :BDNF levels have been extensively studied in various animal models of schizophrenia. It has been shown that animals with neonatal ibotenic acid lesions of the ventral hippocampus or amygdala have decreased BDNF mRNA levels in the prefrontal cortex and hippocampus.66 Gestational methylazoxymethanol acetate (MAM) exposure induced deficits in both the acquisition and retention phases of the Morris maze, and these behavioral changes were associated with significant changes in BDNF.67
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2012, Pharmacology and TherapeuticsExpression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains
2009, Journal of Psychiatric ResearchCitation Excerpt :Allelic variations may also affect BDNF and hippocampal function (Egan et al., 2003; Miyajima et al., 2008) and may be associated with schizophrenia and mood disorders (Levinson, 2006; Neves-Pereira et al., 2005, 2002; Sklar et al., 2002; Szekeres et al., 2003). Decreased hippocampal BDNF mRNA has been reported in animal models of schizophrenia and mood disorders (Angelucci et al., 2005; Ashe et al., 2002; Lipska et al., 2001). However, postmortem studies of hippocampal BDNF mRNA and protein in subjects with schizophrenia have yielded inconsistent results (Brouha et al., 1996; Chen et al., 2001; Durany et al., 2001; Iritani et al., 2003; Knable et al., 2004; Takahashi et al., 2000; Webster et al., 2004, personal communication).
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Present address: Section on Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, Bldg 10, Rm 2D-57, 10 Center Drive, Bethesda, MD 20892, USA.