Glial Response to Perinatal Multi-Hit Stress: The Triggering Factor for Schizophrenia

Abstract

Schizophrenia is a neuropsychiatric disorder with heterogeneous causative agents. This mental disorder is accompanied by impaired cognitive and behavioral abilities, hallucination and negative phenotypes. Among many identified causative agents of Schizophrenia, early life stressors like perinatal protein malnourishment and immune infections are considered to be most efficient. Furthermore, due to the world wide prevalence of protein malnourishment and infections, an individual often encounters them simultaneously, giving rise to a multi-hit condition. In this study, Wistar female rats (3 months old) were broadly divided into control (fed with 20% protein diet) and LP (low protein, fed with 8% protein diet) groups. The F1 pups born to both control and LP females were subjected to single as well as combined exposure of Poly I:C (5mg/kg body weight) and LPS (0.3mg/kg body weight) at PND 3 and 9 respectively. The overall study consists of eight groups i.e., Control, Control+Poly I:C, Control+LPS, Control+Poly I:C+LPS, LP, LP+Poly I:C, LP+LPS and LP+Poly I:C+LPS (multi-hit). All these groups were studied for glial (astrocytes and microglia) changes at PND 12, 21 and 30 and cognitive and behavioral abnormalities at PND 30 respectively. From the overall result, it was seen that both astrocytes and microglia were severely affected mainly in the multihit group, with astrogliosis, astrocytic degeneration and loss of healthy microglial activity being prominent observations. Such cellular abnormalities were followed by severe hyperactivity and memory impairment at PND 30. While such changes were also seen in single-hit group, it was not severe. Such above mentioned abnormalities are also common in Schizophrenia and multi-hit stress was observed to trigger them the most. Thus, this study adds on to Schizophrenic research and concludes that multi-hit stress is the actual triggering factor that leads to development of Schizophrenia in affected individual.