C1q deletion exacerbates stress-induced learned helplessness behavior and induces neuroinflammation in mice

Abstract

Increased levels of pro-inflammatory cytokines have been reported in postmortem brain samples and in the blood of depressed subjects. However, the inflammatory pathways that lead to depressive-like symptoms are not well understood. Using the learned helplessness (LH) model of depression, we examined the role of C1q, the initiator of classical complement pathway in mediating stress-induced depressive-like behavior in mice. We observed no significant changes in social behavior, despair behavior, spatial memory, and aggressive behavior between the wild type (WT) and C1q knockout (KO) mice. However, C1q deletion exacerbated the inescapable electric foot shock-induced learned helplessness behavior in mice. We found significant reductions in C1q mRNA levels in the prefrontal cortex (PFC) of WT helpless mice as compared to the naïve mice. Increased levels of pro-inflammatory cytokines were found in the PFC of C1q KO mice. These findings suggest that classical complement pathway-mediated learned helplessness behavior is accompanied by neuroinflammatory changes under stressful conditions.

C1q as a target molecule to treat human disease: What do mouse studies teach us?

“…C1qKO mice show a pronounced learned helplessness behavior in response to an inescapable foot-shock paradigm, a well-established model to induce depressive-like behavior ( 45 ). Wt mice showed reduced C1q mRNA levels in the prefrontal cortex (PFC) in response to foot-shocks as compared to unshocked mice.…”

“…Wt mice showed reduced C1q mRNA levels in the prefrontal cortex (PFC) in response to foot-shocks as compared to unshocked mice. Interestingly, levels of pro-inflammatory cytokines in the PFC were significantly increased in C1qKO mice independent of the shock paradigm ( 45 ). It remains uncertain, whether these increased cytokines relate to increased levels as seen in post-mortem brain samples of patients or merely reflect an altered balance in the C1qKO brain.…”

“…An increased susceptibility to manifestation of autoimmunity in females was confirmed in double knockout mice for C1q and H2-Bf/C2 -/- ( 80 ) as well as C1q deficiency in the lupus prone MRL/Mp background ( 71 ). Although this effect is particularly well described for autoimmunity on a lupus prone genetic background, it is still noteworthy that a large number of studies in C1qKO mice included in this review investigated female mice only ( 4 , 11 , 38 , 59 , 60 , 62 , 73 , 76 – 79 , 87 , 97 , 116 , 125 , 128 , 146 , 149 , 170 ) while others only used male animals ( 26 , 35 – 37 , 45 , 46 , 50 , 53 , 61 , 63 , 88 , 99 , 110 , 113 , 119 , 141 ) ( Tables 1 – 3 ). Few studies evaluated specifically the differential gender effect ( 12 , 24 , 28 , 55 , 71 , 80 ).…”

Chronic stress and complement system in depression

“… 7 Although C3 deficiency has been shown to attenuate chronic stress-induced behavioral deficits, C1q deficiency exacerbated stress-induced learned helplessness behavior in mice. 8 Furthermore, increased levels of proinflammatory markers have been found in the PFC of C1q knockout mice. 8 These findings suggest that component- and/or pathway-specific effects of the complement system mediate stress-induced behavioral changes.…”

“… 8 Furthermore, increased levels of proinflammatory markers have been found in the PFC of C1q knockout mice. 8 These findings suggest that component- and/or pathway-specific effects of the complement system mediate stress-induced behavioral changes. Moreover, the complement system can be activated in the periphery and/or central nervous system (CNS) following chronic stress.…”