Project Summary/Abstract:
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.