Major depressive disorder (MDD) is a recurring psychiatric disease that causes significant disability and socioeconomic burdens. Current therapies for MDD take weeks to months to be effective, and many patients are treatment-resistant reporting no improvement in symptom severity. In this context, it is important for research to be aimed at understanding the neurobiology of depression and to identify novel therapeutic targets. Clinical and basic research indicate that dysfunction of the medial prefrontal cortex (PFC) is a primary pathophysiological feature that contributes to depressive-like behaviors, including despair, reduced sociability, and cognitive impairment. In particular, studies show that depressive-like behaviors and cognitive impairments are associated with reduced synapse number and dendritic atrophy of pyramidal neurons in the medial PFC. It is well- established that brain-derived neurotrophic factor (BDNF) is an important regulator of neuroplasticity. Indeed mice deficient in BDNF signaling have exaggerated stress-induced neuroplasticity deficits and worsened depressive-like behaviors compared to wild-type mice. Consistent with this work, recent studies show that BDNF signaling in the medial PFC is required for rapid antidepressant-like effects following ketamine or scopolamine. While these studies implicate BDNF in the neurobiology of depression and antidepressant treatment, it remains unclear what cell type drives this neurotrophic signaling. Seminal work has shown that microglia, the tissue-resident macrophages in the brain, actively regulate neuroplasticity in physiological and pathological conditions. Notably, recent studies show that microglia-specific BDNF depletion reduced glutamate receptor expression in the motor cortex, which led to impaired synaptic plasticity in response to a motor learning task. Thus, it is plausible that microglial BDNF is a critical mediator of neuroplasticity in chronic stress and antidepressant treatment. In support of this idea, our initial studies showed that chronic stress reduced BDNF expression in purified microglia in the PFC, which corresponded with synaptic deficits and depressive-like behavior. Further studies showed that ketamine administration increased microglial BDNF expression in the PFC, which was associated with increased dendritic spine density and antidepressant- like behavioral responses. To expound on these findings proposed studies will use mice with microglia-specific BDNF depletion (Cx3cr1CreER:Bdnffl/fl) to test two specific aims: 1) Determine if deficient microglial BDNF confers stress susceptibility via increased synapse loss and depressive-like behaviors following stress; and 2) Examine the role of microglial BDNF in neurobiological responses and behavioral effects of rapid-acting antidepressants ketamine or scopolamine. Studies outlined in this application are significant because they will be the first to study the role of microglial BDNF in neurobiological adaptations underlying both stress-induced depressive-like behaviors and antidepressant treatment. We expect to identify a novel neurotrophic role for microglia, which may guide treatment strategies for MDD and other neurological conditions.
Neuroplasticity deficits in the prefrontal cortex underlie behavioral and cognitive symptoms of Major depressive disorder (MDD). Recent studies demonstrate that microglia, the brain-resident macrophages, actively regulate neuroplasticity through release of soluble factors, including brain-derived neurotrophic factor (BDNF). Proposed studies in this application will examine the role of microglial BDNF in chronic stress-induced depressive-like behaviors and antidepressant responses.
