Molecular signatures of astrocytes and microglia maladaptive responses to acute stress are rescued by a single administration of ketamine in a rodent model of PTSD

Abstract

Stress affects the brain and alters its neuroarchitecture and function; these changes can be severe and lead to psychiatric disorders. Recent evidence suggests that astrocytes and microglia play an essential role in the stress response by contributing to the maintenance of cerebral homeostasis. These cells respond rapidly to all stimuli reaching the brain, including stressors. Using a recently validated rodent model of post-traumatic stress disorder that allows rats to be classified as resilient or vulnerable after acute inescapable footshock stress, we here examined the functional, molecular, and morphological determinants of stress resilience and vulnerability in the prefrontal cortex, focusing on both glial and neuronal cells. In addition, we studied the effects of a single subanesthetic dose of ketamine, a fast-acting antidepressant recently approved for use in treatment-resistant depression and proposed for other stress-related psychiatric disorders. The present results suggest a prompt glial cell response and activation of the NF-κB pathway after acute stress, with an increase in specific cytokines such as IL-18 and TNF-α. This response persists in vulnerable individuals and is associated with a significant change in the levels of critical glial proteins such as S100B, CD11b, and CX43, brain trophic factors such as BDNF and FGF2, and proteins related to dendritic arborization and synaptic architecture such as MAP2 and PSD95. Administration of ketamine 24 h after the acute stress event rescued many changes observed in vulnerable rats, possibly contributing to support brain homeostasis. Overall, our results suggest that glial reactivity, changes in brain trophic factors, and neuronal damage are critical determinants of vulnerability to acute traumatic stress and confirm the therapeutic effect of acute ketamine against the development of stress-related psychiatric disorders.