Brain derived neurotrophic factor deficient mouse: A putative model of allostatic overload.

摘要

Brain-derived neurotrophic factor (BDNF) has profound effects on neuronal plasticity and promotes serotonergic neurotransmission. A deficiency in BDNF has been implicated in the pathophysiology of stress-related psychiatric disorders, such as major depression and anxiety. Increased BDNF signaling is believed to contribute to the therapeutic action of antidepressant treatments. We hypothesized that BDNF deficient mice are vulnerable to mild handling stress and thereby will exhibit depression-like behaviors and relevant neuroendocrine and neurochemical changes. Following acute mild handling stress, male but not female BDNF (+/-) mice showed an increase in duration of immobility in the forced swim test compared to the wild-type mice, which was prevented by treatment with the tricyclic antidepressant desipramine. Following chronic mild handling stress, male BDNF (+/-) mice failed to adapt to stress and continued to exhibit increases in duration of immobility compared to the wild-type controls. Interestingly, female BDNF (+/-) mice also displayed an increase in duration of immobility in the forced swim test, following chronic mild handling stress. Following acute or chronic mild handling stress, BDNF (+/-) mice of either gender, did not exhibit hedonic deficits, in the two bottle choice paradigm. BDNF (+/-) mice did not differ from wild-type mice in the plasma adrenocorticotropic hormone (ACTH) and corticosterone levels at baseline (unhandled condition) or in response to a single intraperionteal injection of saline. We examined the effects of decreased BDNF expression on 5-HT1A receptor number and function at the level of receptor-G protein interaction in serotonergic cell body areas, as well as cortical and limbic areas in mice with a forebrain-specific reduction in BDNF. We observed a significant attenuation of 5-HT1A receptor function, in the absence of a change in coupled, high affinity agonists state of the receptor, in the dorsal hippocampus of BDNF knockout versus control mice. Interestingly, chronic treatment with fluoxetine restored the deficit in 5-HT1A receptor function in CA2/3 and dentate gyrus subregions of the hippocampus. Our data suggest that mice deficient in BDNF could be used as a putative model for allostatic overload, the condition in which chronic stress results in wear and tear of the body.