TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice

Abstract

Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNFα, which contributes to impaired recovery from prolonged learned helplessness.

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

“…Similar can be observed when a TNFα inhibitor, etanercept, is administrated. These observations indicate that the stress-induced GSK3 activation contributes to the disruption of BBB integrity mediated by pro-inflammatory factors, particularly TNFα [70].…”

“…It has been demonstrated that non-ATP-competitive GSK3β inhibitors ameliorate depressive-like behavior in rodents. It has also been shown that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3, whereas treatment with TDZD-8, non-ATP-competitive GSK3 inhibitor, reverses the impaired recovery from learned helplessness [70]. In turn, an ATP-competitive GSK3β inhibitor SB216763 has been found to increase anti-depressant responses in the forced swim test [71], whereas SAR502250 improved the stress-induced physical state in the chronic mild stress test in mice [72].…”

“…It has been also demonstrated that BBB integrity disruption is partially mediated by TNFα, and thus, it has been hypothesized that this factor contributes to blockade of the recovery from prolonged depression-like behavior [70]. An increased level of TNFα in non-recovered mice displaying depression-like behavior is accompanied by greater hippocampal activation of GSK3, higher levels of interleukin-17A and -23, and lower level of the BBB tight junction proteins in comparison to recovered and control animals [70]. The administration of TDZD-8 reduces inflammatory cytokines levels, increases tight junction proteins level, and reverses impaired recovery from depression-like behavior.…”

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

“…We describe here a molecular framework in which cldn5-related epigenetic modifications and transcriptional changes in the NAc lead to stress resilience or vulnerability and depression. In rodents, depression-like behaviors have been associated with increased BBB permeability (7,8) while vascular dysfunction was not observed in those displaying stress resiliency (7,24). However, the cellular and molecular mechanisms involved in this process remained elusive.…”

“…We recently showed that chronic social stress induces blood-brain barrier (BBB) leakiness in the nucleus accumbens (NAc) of male mice, promoting passage of circulating proinflammatory mediators and the establishment of depression-like behaviors, including social avoidance, anhedonia, and helplessness (7). Stress-induced increase in BBB permeability is mediated by loss of tight junction protein claudin-5 (cldn5), a major cell adhesion molecule which forms a paracellular barrier between endothelial cells (7)(8)(9). We showed that CLDN5 expression is reduced in the NAc of depressed patients (7) in line with clinical studies reporting altered cerebrospinal fluid to serum ratio of peripheral markers in depression indicative of greater BBB permeability (10).…”