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

Abstract

Schizophrenia and autism are two severe neuropsychiatric disorders that are associated withprofound cognitive disturbances which considerably contribute to the long-term morbidity andthe decreased ability to function in the society. Currently used therapies do not reach the corecognitive disturbances to a satisfactory extent. Thus, there is a great need for new medicationswith more pronounced effects on the cognitive disturbances. The aim of the present thesis wasto develop and evaluate a behavioural rodent model for cognitive deficits of schizophrenia andautism and use this model to examine the cognitive profile of novel antipsychotic drugcandidates.The predominant pathophysiological hypothesis for schizophrenia postulates a hypofunction ofglutamatergic neurotransmission; deficient glutamatergic signalling has also been discussed in thecontext of autism. Glutamatergic N-methyl-D-aspartate (NMDA) antagonists induce in humanssymptoms reminiscent of those seen in schizophrenia and autism, including cognitive deficits. Inrodents these substances, besides hyperactivity, induce a monotonous and undifferentiatedmovement pattern with only rare switches between behavioural programs. We have speculatedthat this primitivization of the behaviour might correspond to the cognitive deficits observed inautism and schizophrenia. In order to test this hypothesis, mice were rendered hypoglutamatergicby means of administration of the NMDA-receptor antagonist MK-801. These mice were thentreated with either classical antipsychotics, which are often ineffective or even worsen cognitivesymptoms, 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-inducedhyperactivity. However, only the atypical agents reversed the monotonous movement patterninduced by MK-801, in the sense that they to different degrees reintroduced a more variedmovement pattern, particularly with respect to spatial variables like turning. Exploratory rearing,though, was not improved by either the classical or the atypical antipsychotics, which insteadreinforced the MK-801-induced decrease in rearing frequency. The serotonin (5-HT) 2Aantagonist M100907 showed a behavioural profile similar to the atypical antipsychotics withincreased variability with respect to spatial movements, suggesting that 5-HT2A antagonismmight 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 theputative antipsychotic and dopamine stabiliser ACR16.Our results on antipsychotic agents in the present model seem to be in line with their clinicaleffects on cognition; hence it appears that movement pattern analysis of hypoglutamatergic miceindeed has clinical relevance with respect to cognitive deficits of schizophrenia, and possibly alsoautism. Based on the preclinical data presented in this thesis, ACR16 seems to be a promisingcandidate for treating cognitive deficits in these disorders.