Role of Prefrontal Cortex Anti- and Pro-inflammatory Cytokines in the Development of Abnormal Behaviors Induced by Disconnection of the Ventral Hippocampus in Neonate Rats

Front Behav Neurosci. 2018 Oct 22;12:244. doi: 10.3389/fnbeh.2018.00244. eCollection 2018.

Abstract

Neonatal disconnection of ventral hippocampus (VH) outputs in rats has been reported to lead to post-pubertal behavioral and synaptic changes of relevance to schizophrenia. Increased oxidative and inflammatory load in the prefrontal cortex (PFC) has been suggested to mediate some of the effects of neonatal VH lesion (NVHL). In this study, we hypothesized that developmental imbalance of anti- and pro-inflammatory factors within the PFC might affect synaptic development thus contributing to the adult NVHL-induced behavioral deficits. Ibotenic acid-induced excitotoxic NVHL was performed in postnatal day (PD) 7 male Sprague-Dawley rats and the mRNA levels of select pro- and anti-inflammatory cytokines were measured in the medial PFC (mPFC) at two developmental time points (PD15 and PD60). We observed a development-specific increase of pro-inflammatory cytokine, interleukin (IL)-1β mRNA at PD15, and an overall reduction in the expression and signaling of transforming growth factor beta 1 (TGF-β1), an anti-inflammatory cytokine, at both PD15 and PD60 in the NVHL animals. These cytokine changes were not seen in the somatosensory cortex (SSC) or tissue surrounding the lesion site. Daily administration of systemic recombinant TGF-β1 from PD7-14 prevented the appearance of hyperlocomotion, deficits in prepulse inhibition (PPI) of startle and social interaction (SI) in post-pubertal (PD60) NVHL rats. Neonatal supplementation of TGF-β1 was also able to attenuate dendritic spine loss in the layer 3 mPFC pyramidal neurons of NVHL animals. These results suggest that early damage of the VH has long-lasting inflammatory consequences in distant connected structures, and that TGF-β1 has potential to confer protection against the deleterious effects of developmental hippocampal damage.

Keywords: Cytokines; TGF-β1; animal model; behavior; schizophrenia; ventral hippocampus.