Movement pattern analysis of hypoglutamatergic mice A model for cognitive deficits of schizophrenia and autism?

Sammanfattning: Schizophrenia and autism are two severe neuropsychiatric disorders that are associated with pro-found cognitive disturbances which considerably contribute to the long-term morbidity and the decreased ability to function in the society. Currently used therapies do not reach the core cogni-tive disturbances to a satisfactory extent. Thus, there is a great need for new medications with more pronounced effects on the cognitive disturbances. The aim of the present thesis was to develop and evaluate a behavioural rodent model for cognitive deficits of schizophrenia and au-tism and use this model to examine the cognitive profile of novel antipsychotic drug candidates. The predominant pathophysiological hypothesis for schizophrenia postulates a hypofunction of glutamatergic neurotransmission; deficient glutamatergic signalling has also been discussed in the context of autism. Glutamatergic N-methyl-D-aspartate (NMDA) antagonists induce in humans symptoms reminiscent of those seen in schizophrenia and autism, including cognitive deficits. In rodents these substances, besides hyperactivity, induce a monotonous and undifferentiated move-ment pattern with only rare switches between behavioural programs. We have speculated that this primitivization of the behaviour might correspond to the cognitive deficits observed in autism and schizophrenia. In order to test this hypothesis, mice were rendered hypoglutamatergic by means of administration of the NMDA-receptor antagonist MK-801. These mice were then treated with either classical antipsychotics, which are often ineffective or even worsen cognitive symptoms, or so called atypical agents that seem to have some beneficial effects on cognition. The behaviour was video taped and analysed with a video tracking software. Both classical and atypical antipsychotic compounds effectively blocked MK-801-induced hyper-activity. However, only the atypical agents reversed the monotonous movement pattern induced by MK-801, in the sense that they to different degrees reintroduced a more varied movement pattern, particularly with respect to spatial variables like turning. Exploratory rearing, though, was not improved by either the classical or the atypical antipsychotics, which instead reinforced the MK-801-induced decrease in rearing frequency. The serotonin (5-HT) 2A antagonist M100907 showed a behavioural profile similar to the atypical antipsychotics with increased variability with respect to spatial movements, suggesting that 5-HT2A antagonism might contribute to some of the beneficial effect on cognition of atypical antipsychotic agents. The only tested compound that increased exploratory rearing in the MK-801-treated mice was the putative antipsychotic and do-pamine stabiliser ACR16. Our results on antipsychotic agents in the present model seem to be in line with their clinical effects on cognition; hence it appears that movement pattern analysis of hypoglutamatergic mice indeed has clinical relevance with respect to cognitive deficits of schizophrenia, and possibly also autism. Based on the preclinical data presented in this thesis, ACR16 seems to be a promising candidate for treating cognitive deficits in these disorders.