Novel susceptibility pathways and drug targets for psychosis

Nikos Daskalakis

Schizophrenia is a complex mental disorder often characterised by social dysfunction, breakdown of thinking, and a loss of contact with reality. It usually begins in early adulthood and is associated with disturbed neurodevelopment.  Genetic risk-factors are clearly involved and the role of non-genetic factors is debated (van Os & McGuffin, 2003). The perinatal period, as a time of rapid development, plasticity and vulnerability to environmental influences, as well as additional cumulative exposure to psychosocial stressors are of special interest (McDonald & Murray, 2000; van Winkel, Stefanis, & Myin-Germeys, 2008).

This so-called “three-hit model” of psychopathology is defined as the interaction between [1] predisposing genes, and [2] early-life experience and [3] later-life cognitive/emotional inputs. It is thought that this interaction may produce a vulnerability or resilience to psychopathology.


-       To show the importance of early-life adversity on the neonate’s stress response, dam’s care and pre-adult/adult behaviour in outbred rat populations.

-       To observe the naturally occurring maternal environment in rat families genetically predisposed for behavioural features of psychosis. The phenotype of the offspring will be correlated with the dam’s behaviour and genotype.

-       To manipulate in such families the early- and later-life environment in order to attenuate or to enhance the behavioural features of psychosis.

In the final stage of the project, we will have a nature-nurture rat model for schizophrenia valid for pathway identification and investigation of epigenetic influence on psychopathology.