Abstract
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH) users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous (HET) mutant mice has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and wildtype (WT) littermates were treated during young adulthood with METH and, following a 2-week break, prepulse inhibition (PPI) was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH) disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine (APO) or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioral endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behavior. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the disorder.
Highlights
Schizophrenia is a debilitating neuropsychiatric disease, and despite numerous factors being associated with disease risk and pathophysiology, the etiology of the illness is poorly understood
The key findings of the current study were that (1) compared to WT controls, brain-derived neurotrophic factor (BDNF) HETs showed reduced baseline prepulse inhibition (PPI), irrespective of METH pre-treatment or the sex of the animals; (2) male BDNF HETs showed greater sensitivity to the disruptive effects of an AMPH challenge on PPI at the 30 ms inter-stimulus interval (ISI), irrespective of whether they had been pre-treated with METH; (3) female mice pre-treated with METH showed a relative tolerance to the effects of AMPH on PPI at the 30 ms ISI, irrespective of their genotype
There were no interactions between METH treatment and BDNF depletion on PPI, and no changes were observed in the PPI-disrupting effects of APO and MK-801 in this model
Summary
Schizophrenia is a debilitating neuropsychiatric disease, and despite numerous factors being associated with disease risk and pathophysiology, the etiology of the illness is poorly understood. Post-mortem studies have consistently shown reduced BDNF expression in the hippocampus and dorso-lateral prefrontal cortex (DLPFC) of patients with schizophrenia, two brain regions that are highly implicated in the pathophysiology of the disorder (Takahashi et al, 2000; Weickert et al, 2003; Hashimoto et al, 2005; Wong et al, 2010; Thompson Ray et al, 2011) These findings have lead to numerous studies aiming to asses peripheral BDNF as a biomarker for the illness, and a recent meta-analysis found a moderate decrease in blood BDNF levels in drug-naïve and medicated schizophrenia patients (Green et al, 2011). It has recently been proposed that altered BDNF signaling in the disorder may contribute to these sex differences (Hill, 2012)
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