Prenatal immune challenge induces behavioral deficits, neuronal remodeling, and increases brain nitric oxide and zinc levels in the male rat offspring

Neuroscience. 2019 May 15;406:594-605. doi: 10.1016/j.neuroscience.2019.02.018. Epub 2019 Feb 21.

Abstract

Schizophrenia is a severe mental disorder with numerous etiological susceptibilities. Maternal infection is a key risk factor for schizophrenia. Prenatal lipopolysaccharide (LPS) infection stimulates cytokine production that affects brain development. In the present study, we aimed to investigate the effect of prenatal LPS injection at gestational day (GD) 14-16 on behavioral paradigms, and neuronal morphology in the prefrontal cortex (PFC), basolateral amygdala (BLA), nucleus accumbens (NAcc) and ventral hippocampus (VH) at two critical ages of development: pre-pubertal (postnatal day 35, PD35) and post-pubertal (PD60) age in male rats. We also evaluated the effects of LPS on nitric oxide (NO) and zinc (Zn) levels in seven brain areas (PFC, VH, amygdala, brainstem, striatum and dorsal hippocampus) at PD35 and PD60. LPS induced hyperlocomotion in a novel environment and reduced social contact as well as increased the levels of NO and Zn in the PFC, brainstem and amygdala as observed in other animal models of schizophrenia-related behavior. Furthermore, we found that LPS-treated rats presented post-pubertal neuronal hypertrophy in the PFC and BLA and decreased spine density in the NAcc. The neuronal morphology of neurons in the VH in LPS-treated rats remained unaltered. Interestingly, the anxiogenic-related behavior correlated with neuronal hypertrophy observed in the BLA. Our findings suggest that the behavioral and neural modifications observed in our model could be mediated by the long-lasting alterations in Zn and NO levels in the brain.

Keywords: Golgi-Cox staining; amygdala; anxiety; maternal infection; schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Animals
  • Animals, Newborn
  • Brain / drug effects*
  • Brain / immunology
  • Central Nervous System Stimulants / pharmacology
  • Female
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Lipopolysaccharides / pharmacology*
  • Male
  • Motor Activity / drug effects
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / immunology
  • Nitric Oxide / metabolism*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / immunology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / immunology
  • Rats, Sprague-Dawley
  • Zinc / metabolism*

Substances

  • Central Nervous System Stimulants
  • Lipopolysaccharides
  • Nitric Oxide
  • Zinc