Lecture: Jørgen Scheel-Krüger
Autism: Animal models related to its neurobiology, anatomy and neurotransmitters
Professor Jørgen Scheel-Krüger
CFIN, Aarhus University Hospital, Denmark
Social dysfunction represents a key feature in several psychiatric disorders, including autism, schizophrenia, depression and drug dependency. Unfortunately, these most debilitating human behavioural disorders are all in need of better treatment alternatives than those currently available.
Social interactions are performed by all species of the animal kingdom and are essential for survival. It is thus imperative for the development of effective drug treatments of social dysfunctions that we study social behaviour across species, which can later be translated to the human condition. In humans, it is well known that prenatal exposure to the GABA facilitating antiepileptic drug VPA is associated with a high risk for cognitive dysfunction, including autism spectrum disorders in addition to somatic malfunctions.
Recent data from our team suggest that prenatal exposure of valproate (VPA) could provide an animal model for autism and impairment of social interaction. In our subchronic treatment model pregnant rats received a VPA daily in the clinically relevant doses of 20 or 100mg/kg from day 9 or 12 until the end of pregnancy. This model is thus designed to mimic the human clinical condition with VPA administered chronically to pregnant epileptic women. Our model differs from the original VPA model in which only one single high neurotoxic dose of VPA (400-600mg/kg) is injected at day 12.5 of pregnancy and causes losses of neurons and behavioural changes (for review, see Roullet et al., 2013). In contrast, we observed increased numbers of cortical neurons in the offspring, a finding we suggest may be related to a trophic effect of GABA on the migration of early embryonic cells in fetal brain tissue. Our increased cell number finding is consistent with the results of Courchesne et al., 2011 reporting an abnormally high number of neurons in the prefrontal cortex of autistic males.
In our model, we observed decreased juvenile play behaviour in young, male VPA rats, consistent with the social deficit observed in human autism. VPA-rats had markedly decreased levels of striatal serotonin, consistent with the involvement of serotonin in social play behaviour. Adult VPA rats showed enhanced performance in the object recognition test. Preliminary results on the receptor binding profile of the essential social neurotransmitter oxytocin will also be presented.