Brain-derived neurotrophic factor (BDNF) mRNA in rats with neonatal ibotenic acid lesions of the ventral hippocampus

Abstract

Increasing evidence suggests that schizophrenia is a neurodevelopmental disorder with a progressive course characterized by worsening of symptoms and morphological alterations within the brain. This suggests that a neurodegenerative component may exist in schizophrenia. The role of brain-derived neurotrophic factor (BDNF) in neurodevelopment, cell viability and synaptic plasticity led to the investigation of BDNF as a potential candidate molecule in the pathophysiology of schizophrenia. BDNF mRNA was examined by in situ hybridization in the prefrontal cortex and hippocampus of animals with neonatal ibotenic acid lesions of the ventral hippocampus, a putative neurodevelopmental animal model of schizophrenia. Results demonstrate that animals with neonatal ibotenic acid lesions of the ventral hippocampus have reduced basal levels of BDNF mRNA. It is possible that alterations in this trophic factor render animals more susceptible to neurodegenerative insults.

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.