New data in an animal model for schizophrenia: Ketamine-induced locomotor activity and repetitive behavioural responses are higher after neonatal functional blockade of the prefrontal cortex

Schizophrenia is a complex mental illness, with a higher risk of onset among young men. Schizophrenia is nowadays considered to result from a defective connectivity, having a neurodevelopmental origin, between several integrative regions. Morphological anomalies consistent with early brain development disturbances have been described at the level of the patients'left prefrontal cortex (PFC). Furthermore, psychotomimetic such as the noncompetitive NMDA/glutamate receptor antagonist ketamine, can induce psychotic symptoms in healthy subjects and exacerbate them in schizophrenia patients.

Taking into account all the above points the present animal modelling study aimed to precisely investigate effects of ketamine in young adult male rats on behavioural responses, following neonatal functional blockade of the left PFC (infralimbic/prelimbic region). Functional inactivation of the left PFC was carried out by local Tetrodotoxin (TTX) microinjection in 8-day-old (PND8) rats. In these animals, at adulthood, locomotor activity and repetitive behaviours (left- and right-rotation, head weaving, intense sniffing, self-grooming) were investigated after sc administration of 3 different doses of ketamine.

Main significant results obtained during 1 hour after ketamine doses were as follows : Doses-dependent effects were observed for the different behavioural parameters; higher increases were observed in TTX groups, compared to control groups, only for locomotor activity and left-rotation.

Results obtained with these two latter parameters strongly suggest that animals subjected to TTX functional inactivation in the left PFC at PND8 present increased responsiveness to ketamine. These findings may further new insights for the animal modelling of the pathophysiology of schizophrenia involving early functional disruption of the prefrontal cortex.