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.

Antoneta T Joseph,Lalit K Srivastava,Sanjeev K Bhardwaj

doi:10.3389/fnbeh.2018.00244

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.

Highlights

Disrupted functional connectivity between the hippocampus and the prefrontal cortex (PFC), presumably of developmental origin, is considered a core deficit in schizophrenia and other neurodevelopmental psychiatric disorders (Godsil et al, 2013; Bähner and Meyer-Lindenberg, 2017)
Given that a critical balance of pro- and anti-inflammatory cytokines is important for neural functions (Spulber et al, 2009; Yamato et al, 2014) and alterations in pro- and anti-inflammatory cytokines have been reported in the brain and cerebrospinal fluid (CSF) of schizophrenia patients (Trépanier et al, 2016; Wang and Miller, 2018), we hypothesized that alterations in this balance in neonatal VH lesion (NVHL) animals could be involved in synaptic and behavioral changes
We observed a reduction in the expression and signaling of TGF-β1 and an increase in the expression of IL-1β mRNA in the medial PFC (mPFC) of NVHL animals during neonatal and post-pubertal periods suggesting a persistent increase of inflammatory load in distant connected structures following neonatal lesion of the ventral hippocampus (VH)

Summary

Introduction

Disrupted functional connectivity between the hippocampus and the prefrontal cortex (PFC), presumably of developmental origin, is considered a core deficit in schizophrenia and other neurodevelopmental psychiatric disorders (Godsil et al, 2013; Bähner and Meyer-Lindenberg, 2017). Monosynaptic glutamatergic afferents from the CA1 and subiculum of the ventral hippocampus (VH) to the medial PFC (mPFC; Thierry et al, 2000), form a critical pathway mediating the communication between the two structures This interaction between the VH and the mPFC begins early in life (first postnatal week) in the form of theta-gamma coupled oscillations (Brockmann et al, 2011). Increase in inflammatory responses and oxidative stress were suggested to play a critical role in the abnormal maturation of PV neurons in NVHL rats (Cabungcal et al, 2014) Consistent with this idea, we recently reported a developmentspecific effect of the NVHL on mPFC microglial reactivity and expression of genes implicated in oxidative stress and synaptic pruning (Hui et al, under review). Given that a critical balance of pro- and anti-inflammatory cytokines is important for neural functions (Spulber et al, 2009; Yamato et al, 2014) and alterations in pro- and anti-inflammatory cytokines have been reported in the brain and cerebrospinal fluid (CSF) of schizophrenia patients (Trépanier et al, 2016; Wang and Miller, 2018), we hypothesized that alterations in this balance in NVHL animals could be involved in synaptic and behavioral changes

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Conclusion