Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis

Abstract

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

“…Studies in BDNF deletion mice have been mixed, whereas deletion of TrkB in neural progenitor cells is reported to block the proliferation of newborn neurons [26,27]. Localized BDNF knockdown using RNA interference is reported to block the differentiation but not proliferation of newborn neurons [16]. Blockade of TrkB by the expression of dominant negative TrkB or deletion of TrkB in progenitor cells also blocks antidepressant-induction of neurogenesis [27,28].…”

“…However, a recent study using RNA interference to knockdown BDNF expression in subregions of the hippocampus reports depressive behaviours in the forced swim and sucrose preference tests [16]. The discrepancy between these studies could be due to different knockdown approaches as well as behavioural methodology [16]. In addition, region-specific effects of BDNF (antidepressant effect in the hippocampus, but a pro-depressive effect in the nucleus accumbens) could influence behavioural outcomes particularly in mutant mouse models where knockout is global and not localized to a particular brain region [6,7].…”

Social regulation of adult neurogenesis in a eusocial mammal

“…Previous studies on social status and the stress system in this species have yielded inconsistent results, with subordinates having higher cortisol in one study (Clarke and Faulkes, 1997) but not in others (Clarke and Faulkes, 1998;Clarke and Faulkes, 2001). Moreover, instead of displaying the depressive-like behavioural profile typically associated with chronic stress and low levels of neurogenesis (Gould et al, 1997;Fuchs and Flügge, 2002;Thomas et al, 2007;Liu et al, 2008;Taliaz et al, 2009;Snyder et al, 2011;Pinheiro et al, 2013), subordinate naked mole-rats are highly active, participating in burrowing, foraging, colony defense, and pup care (Sherman et al, 1991). These departures from the typical dominant/subordinate dynamic are not necessarily surprising.…”

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

“…The neurotrophic hypothesis of depression is based on clinical and preclinical observations that include three lines of evidence: a low concentration of BDNF in the hippocampus of postmortem samples from depressed suicide victims [74] , depression-related behaviors caused by impaired BDNF signaling in rodent hippocampus [75,76] , and the antidepressant effects of increased hippocampal BDNF [77,78] . BDNF is critical for stabilizing synaptic plasticity.…”