Animal model of differential susceptibility to stress in development: implications for schizophrenia

Abstract

Rationale/statement of the problem : Common gene variants predisposing for altered dopamine (DA) neurotransmission are candidates for schizophrenia-susceptibility genes, although genome-wide studies so far showed a weak association of these variants with schizophrenia. It has actually become apparent that the expression of psychotic symptoms in schizophrenia is associated with the exposure of the genetically predisposed individuals to environmental risk factors during development such as early life adversity and upbringing in an unfavorable social environment. Furthermore, it has been postulated that genetic predisposition can promote not only vulnerability in response to negative environmental input, but also resilience in response to positive environmental stimulation. Methods : We decided to test this hypothesis in the apomorphine-susceptible (APO-SUS) rat line, which was selected from Wistar rats on the basis of an extremely enhanced stereotypic gnawing response to administration of the dopamine agonist, apomorphine (APO-gnawing). The parental strain was used for comparison. Adult rats exposed as pups to poor maternal care and to post-weaning social-isolation rearing were examined for pre-pulse inhibition of acoustic startle (PPI), T-maze spontaneous alternation, contextual fear-conditioning and stress hormonal responses to a conditioned emotional stressor. Results : Adult APO-SUS rats that had experienced poor maternal care as judged from low maternal licking and grooming (LG) scores showed dramatically enhanced stress-induced ACTH levels in the face of modest increases in circulating corticosterone (CORT) and prolactin levels. These low LG offspring also developed a basal PPI-deficit, reduced acoustic startle and impaired contextual fear-conditioning, but showed enhanced short-term memory. Additional isolation rearing abolished entirely basal PPI and impaired short-term memory in these individuals. High LG offspring, on the contrary, displayed enhanced PPI in both rearing conditions that was reduced only after CORT-challenge, while the low LG was resistant to CORT. Maternal LG history alone in Wistar rats had limited effects on the behaviour or stress response of offspring. When low maternal LG history was combined with post-weaning social isolation, basal APO-gnawing was decreased and PPI increased. High LG offspring reared in isolation displayed, however, the highest APO-gnawing and the lowest PPI levels among rats reared in social isolation. An injection of high dose CORT in the adult low LG offspring reduced PPI, whereas the high LG group was resistant to the acute effects of CORT. Conclusion : If exposure to negative social environment accumulates, a schizophrenia-like phenotype, characterized by a severe deficit in sensorimotor gating and brain glucocorticoid-resistance, precipitates in the genetically predisposed individuals while the non-predisposed individuals are resilient. However, the same genetically predisposed individuals are sensitive to positive environment as well, where they improve their phenotype and outperform the controls, which do not change. This is the first animal model to find strong evidence for a differential susceptibility to stress in development depending on genetic predisposition.

Keywords

• animal model
• schizophrenia
• maternal behavior
• cortisol
• offspring