Verhaltenspharmakologische Untersuchungen zur Auswirkung neonataler Läsionen des entorhinalen Cortex auf kognitive Leistungen adulter Ratten

Abstract

The entorhinal cortex (EC) is involved in a variety of cognitive functions by virtue of its neuronal input from the neocortex and projection to the hippocampal formation and the limbic-striatal system. Neonatal lesions are increasingly considered useful models for disconnection syndromes such as schizophrenia. Thus, the effects of neonatal EC lesions on adult rat behavior were investigated. Bilateral neonatal (postnatal day 7) lesions were induced by microinjection of ibotenic acid into the EC. Naïve and sham-lesioned (PBS only) rats served as controls. Adult rats were tested for spatial learning in an 8-arm radial maze and for motivation. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) and locomotor activity were assessed with and without apomorphine (APO) challenge and before and after repeated MK-801, PPI also after acute low dose MK-801. Finally, the brains were histologically processed to detect brain tissue damage. Neonatal lesions produced thinning of tissue in the EC and reduced myelination and the density of parvalbumin-immunpositive cells in the hippocampus and the amygdala. They increased perseveration only in a delayed task in the radial maze, induced a working memory deficit during an allocentric and egocentric task and also reduced breakpoints in operant responding. Lesions did not alter baseline locomotor activity, but enhanced the locomotor stimulating effect of APO. PPI was not affected by the lesion with and without APO challenge. However, EC-lesions prevented the PPI-disruptive effect of acute low dose MK-801. Locomotor activity was reduced after MK-801 treatment in all groups but no effect on PPI was found. Neonatal lesions of the EC induced neuroanatomical changes, behavioral deficits and dysregulation of dopaminergic and glutamatergic functions that are characteristic in schizophrenic patients. Thus, neonatal lesions of the EC may serve as an animal model for certain aspects of neurodevelopmental disturbances, e.g. schizophrenia.