Altered expression of brain-derived neurotrophic factor (BDNF) has been implicated in schizophrenia and depression. Multiple disruptions along the neurodevelopmental axis may contribute to these illnesses. We therefore developed an animal model where Wistar rats are subjected to an early stress, 24-hour neonatal maternal deprivation, and a late stress, simulated by chronic young-adult glucocorticoid treatment. These ‘two-hit’ animals showed significant 20-30% reduction of BDNF expression in the dentate gyrus and CA1 and CA3 regions of the hippocampus, as well selective cognitive deficits.
Prepulse inhibition (PPI) is a measure of sensory gating which is deficient in schizophrenia and other psychiatric illnesses. ‘Two-hit’ rats showed no change in baseline PPI but attenuation of dopaminergic control of PPI. We then assessed PPI regulation in mice heterozygous for a mutation in the BDNF gene (BDNF Het). Baseline PPI was not different between BDNF Het and wildtype controls. Treatment with a range of dopaminergic or serotonergic drugs, such as apomorphine, amphetamine, fluoxetine or fenfluramine, altered PPI to a similar extent in BDNF Het and wildtype mice. These studies show that, unlike in patients with schizophrenia or in the ‘two-hit’ rat model, in genetically-modified mice significant reduction of BDNF expression in the brain is not associated with disrupted regulation of PPI. Further studies are on-going in mice to address the cumulative effect of developmental stress in addition to genetic modification of BDNF expression.
Using behavioural animal models, these studies provide insight into the role of altered BDNF levels in the brain in schizophrenia and depression.