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

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.

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…It is interesting that MIA is a risk factor for both SCZ and ASD, since some of the neurological deficits observed in these disorders appear to be opposing. For example, SCZ is characterized by a significant loss of gray matter resulting in hypoconnectivity between the anterior hippocampus and PFC (Vita et al, 2012;Blessing et al, 2020), on which the neonatal ventral hippocampal lesion rodent model of SCZ is based (Joseph et al, 2018), whereas ASD is associated with hyperconnectivity (Supekar et al, 2013). How could the same risk factor play a role in such opposing phenotypes?…”

Loss of dysbindin-1 in excitatory neurons in mice impacts NMDAR-dependent behaviors, neuronal morphology and synaptic transmission in the ventral hippocampus

“…Brain sections were mounted on gelatin-coated slides, lightly pressed and kept at 4 °C in dark moist container for 7 days, clarified, and then cover slipped using Permount following FD Rapid GolgiStain kit guidelines. Slides were allowed to dry for two weeks before neuron tracing was performed using a Zeiss Observer Z1 MBF Microscope and Neurolucida Software (MBF Bioscience) 41 . Approximately 3 hippocampal vCA1 neurons per mouse were traced, from different sections and locations of the ventral hippocampus.…”

Advantages and Limitations of Animal Schizophrenia Models

“…Numerous studies have shown that NVHL rats exhibit impaired behavior. NVHL rats display impaired sensorimotor gating [ 200 , 202 , 203 ], social interactions [ 203 , 204 ], attention [ 205 ], working memory [ 206 , 207 ], spatial memory [ 208 , 209 ], hyperlocomotion [ 204 , 210 , 211 ], and hypersensitivity to psychostimulants [ 200 , 212 ]. Additionally, NVHL animals show enhanced addictive behavior, such as increased self-administration of cocaine, nicotine, alcohol, and methamphetamine [ 213 , 214 , 215 , 216 ].…”

“…Several studies have shown disturbed cytokine levels in the NVHL rat model. Increased levels of proinflammatory IL-1β and decreased levels of transforming growth factor-β1 (TGF-β1), an anti-inflammatory cytokine, have been observed; however, there are no significant changes in TNF-α or IL-6 [ 203 ]. Feleder et al [ 224 ] used lipopolysaccharide (LPS) to develop NVHL and found a significant increase in TNF-α, interleukin-1 (IL-1), and interleukin-2 (IL-2) in brain structures, such as the nucleus accumbens, prefrontal cortex, and hippocampus, indicating long-lasting inflammatory responses in brain structures involved in schizophrenia pathophysiology.…”