**4.3 Models with hyperinflammation**

Intraperitoneal injection in rodents of kynurenine (100 mg/kg) resulting in a 37-fold CNS enhancement likely leading to immune system activation was associated with a higher rate of error in the radial arm maze, although no alteration was found in locomotor function or the latency to obtain food reward [147]. When kynurenine was applied on postnatal days 7−10 and rats were evaluated as adults' social neurobehavior and locomotor activity was attenuated; however, no effects on attention or fear conditioning were detected [148].

While the dosages of kynurenine utilized in these studies were high, the outcomes suggest that neuroinflammation can affect cognitive function, which could involve astrocytes [137], and that early life activation of the processes of neuroinflammation can have long-lived consequences. Further evidence of this is provided by data showing that infection by *Toxoplasma gondii* (*T. gondii*) is a predisposing factor for

SCZ [149]. *T. gondii* induces the synthesis of KYNA, potentially in astrocytes [150]. *T. gondii* involvement may play a role in the disease by enhancing KYNA synthesis within astrocytes. While *T. gondii*-infected animals have exhibited SCZ-like neurobehaviors in multiple studies, the contribution of KYNA or other astrocyte-related elements needs further study because the parasite exerts a plethora of direct and indirect influences on the brain [151].

Short-term one-week exposure of mice to cuprizone resulted in flawed working memory and augmented responses to methamphetamine and phencyclidine. These cognitive behaviors were associated with perturbation of astrocytes/microglia and enhancement of IL-6 in GFAP+ cells as well as an increase in other proinflammatory biomarkers, which have been observed in SCZ [152].

The production of many proinflammatory elements is mediated through the transcription of nuclear factor-kappa B (NF-κB) [153]. Several genetic, biomarker, and postmortem data indicate the role of NF-κB in SCZ. In transgenic rodents in which NF-κB function was specifically blocked in astrocytes while there were no differences in overall health outcomes, locomotor function, sensorimotor actions, or anxiety, female GFAP-IκBα-dn rodents exhibited mild deficiencies in the terminal stage of the non-cued type of the Barnes maze, as corroborated via the increased latency to the first correct nose poke and reduced time length in the portion of the maze already enclosing the goal box [154].
