The effect of early life immune challenge on adult forced swim test performance and hippocampal neurogenesis.

Many psychiatric diseases can be considered neurodevelopmental in nature and accumulating evidence links immune system dysfunction to disease etiology. Yet, it is currently unknown how the immune system alters brain function through development to increase susceptibility to psychiatric illness. Neonatal immune challenge in rodents is a neurodevelopmental model that has been associated with long-term molecular and behavioural changes in stress-reactivity. As enhanced stress-reactivity is associated with the emergence of depressive-like behaviours concurrent with hippocampal pathology, we measured depressive-like behaviour in the forced swim test and hippocampal neurogenesis in adult mice neonatally exposed to lipopolysaccharide LPS; 0.05 mg/kg, i.p. on postnatal days 3 and 5. As there are important functional differences along the ventral-dorsal hippocampus axis, ventral and dorsal hippocampal neurogenesis were measured separately. Our findings reveal a sexually-dimorphic response to early-life LPS challenge. Male LPS-mice spent less time immobile in the forced swim test, suggesting altered reactivity to swim stress. This was accompanied by an increase in doublecortin-positive cells in the dorsal hippocampus of female mice. These findings demonstrate that exposure to an immune challenge during critical developmental time periods leads to long-term sexually-dimorphic alterations in stress-reactivity that are accompanied by changes to adult hippocampal neurogenesis.

Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma.

Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163-, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.