Role of Brain-derived Neurotrophic Factor in Depression-related Behaviour – Could it Explain the Higher Incidence in Females?

Linkage analyses demonstrate that major depressive disorder (MDD), a leading debilitating disease comprising 20–50 % of the psychiatric disorder diagnoses worldwide, has an approximately 50 % genetic component.¹ Notably, the occurrence of MDD is twice as prevalent in women compared with men,^2,3 although the underlying reason for this difference is currently unknown. It may be that men and women show distinct patterns of genetic predisposition for precipitating MDD; alternatively, it may be that women have a unique biology, which impacts genes differentially in response to causes of MDD compared with men. It is likely that women suffer from MDD more than men because of a combination of these two reasons. Clinical studies show that depression is a common symptom of disorders associated with menstrual cycle stages,^4,5 and that female rodents are more prone to depression during certain phases of the oestrous cycle.⁶ However, we also know that stress contributes to the occurrence of MDD⁷ and that the stress response is highly influenced by sexually dimorphic hormone composition.^8–10 Therefore, to distinguish the role of specific genes critical for MDD and account for its prevalence in women, it is necessary to identify which genes are differentially regulated between males and females, both at baseline and in response to stress.

Recent work suggests that the growth factor brain-derived neurotrophic factor (BDNF) may fulfil criteria for a gene that is both important in depression and regulated in a sexually dimorphic manner. Human studies reveal that BDNF messenger RNA (mRNA) expression is decreased in the cortex and hippocampus of suicide victims,¹¹ and that serum levels of BDNF in patients are increased by antidepressant treatment coincident with relief of MDD symptoms.¹² Furthermore, preclinical studies have shown that antidepressant treatment increases hippocampal expression of BDNF,¹³ and that infusion of BDNF directly into the dentate gyrus or CA3 subregion of the hippocampus is sufficient to induce a behavioural antidepressant response.¹⁴ Additionally, BDNF heterozygous models¹⁵ and various BDNF knockout models demonstrate the necessity of hippocampal-expressed BDNF for behavioural antidepressant responses.^16–18 These data support the ‘neurotrophic hypothesis of depression’, which states that loss of BDNF expression from the hippocampus may trigger functional alterations that underlie aspects of depression-related behaviour, while antidepressants may mediate therapeutic effects in part by increasing levels of BDNF in this region of the brain.¹⁹

Role of Brain-derived Neurotrophic Factor in Antidepressant Efficacy and Depression in Males
There have been numerous studies examining the neurotrophic hypothesis of depression in male rodents. Many preclinical studies start with male animals, because the use of female subjects may be complicated by oestrous phases and behavioural and neurochemical changes have been documented in females at each phase of the oestrous cycle. In addition, for some stress studies, male mice are preferred for their aggressive and territorial behaviours. The neurotrophic hypothesis of depression proposes two main predictions:

• BDNF is necessary and sufficient for antidepressant efficacy; and
• BDNF is required for normal depression-related behaviour.

BDNF constitutive knockout in mice is embryonically lethal; thus, to investigate the role of BDNF in depression and antidepressant action, other genetic approaches have been developed. As previously mentioned, several genetic models of BDNF deficiency in the brain confirm that BDNF is necessary for antidepressant efficacy. In a forebrain-specific BDNF knockout mouse line that has a 60 % decrease in BDNF expression in the hippocampus,¹⁶ or in mice in which a viral-mediated deletion of BDNF was induced selectively in the dentate gyrus subregion of the hippocampus,¹⁷ a loss of antidepressant efficacy was observed in the forced swim test. Briefly, the forced swim test is a model of acute inescapable stress in which escape behaviour manifests as swimming and despair response is measured as immobility. In this behavioural paradigm, antidepressants are known to increase escape behaviour. Conversely, in studies, directly infusing BDNF into the midbrain²⁰ or into either the CA3 or dentate gyrus subregions of the hippocampus¹⁴ results in increased struggling, which suggests an antidepressant response. Taken together, these data illustrate that, at least in male subjects, BDNF is necessary for antidepressant efficacy.