Abstract
Brain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF’s role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/−) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/− mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/− mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/− mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.
Highlights
Schizophrenia is a neuropsychiatric disorder associated with life-long disabilities and a reduced life expectancy[1]
While overall attentional set-shifting task (ASST) performance in brain-derived neurotrophic factor (BDNF)+/+ mice was not affected by EE housing, performance in the reversal phases was improved by EE (t = 2.17, P = 0.045, see Supplementary Fig. 2)
Increasing evidence led to the hypothesis that the neurotrophin BDNF is involved in behavioral endophenotypes of schizophrenia[23,24,25,28,29,30,31,37]
Summary
Schizophrenia is a neuropsychiatric disorder associated with life-long disabilities and a reduced life expectancy[1]. Schizophrenia is a neurodevelopmental disorder, caused by a combination of genetic susceptibility. Some neuropathological features of schizophrenia are correlated with reduced levels of brain-derived neurotrophic factor (BDNF). BDNF belongs to the protein family of neurotrophins and is secreted by neurons[6,7]. BDNF is involved in the survival, development, and differentiation of neurons and is crucial for synaptic plasticity[6,8,9,10]. A plethora of findings demonstrated a pivotal role of BDNF in learning and memory[11,12,13,14,15]. Studies using heterozygous BDNF-deficient mice and mice carrying the val66met
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