ABSTRACT BACKGROUND: Disconnections in cortical-related networks, the neuronal circuits of higher-order brain operations (attention, cognition, memory and perception), are thought to underlie dysfunctions of conscious integration such as those seen in schizophrenia. More than 80% of the neurons that make up these complex systems are glutamatergic. Clinical and experimental evidence suggest that NMDA-type glutamate receptors are implicated in the pathophysiology of schizophrenia. Cognitive impairment and schizophrenia-like symptoms (hallucinations and psychosis) are produced in humans by the administration of a single subanaesthetic dose of ketamine, a non-competitive NMDAr antagonist like phencyclidine and MK-801. The neuronal mechanisms underlying transient disruption in NMDAr function remains unknown. / Disorders of cognition-related coherences of gamma frequency (30-80 Hz) oscillations between cortical areas are a major functional abnormality in schizophrenic patients. Ketamine and MK-801, non-competitive NMDA receptor antagonists, abnormally and dose-dependently increase the power of wake-related, spontaneously occurring gamma oscillations in the electro-encephalogram (EEG) of the rat neocortex and concomitantly induces abnormal behaviour relevant to schizophrenia, including hyperlocomotion and ataxia. This observation is consistent with findings obtained in humans supporting the hypothesis that pathological (abnormal increased synchronization in) gamma oscillations are correlated with psychotic symptoms. / Schizophrenia-like psychosis of epilepsy (interictal psychosis) occurs in 3%–7% of patients with epilepsy including those with generalized non-convulsive absence epilepsy. Patients with generalised epilepsy have been reported to have an increased the power of their gamma frequency activity on the EEG. Ketamine and MK-801 also dose-dependently suppress SWD and concomitantly induces hyperlocomotion in WAG/Rij rats, genetic rat model of absence epilepsy. Thus, the study also investigated gamma oscillations in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and the effect of NMDA receptor antagonists. / METHODS: The relationship between quantitative measures of gamma power and locomotion was assessed in 8 freely moving rats following single injections of ketamine (<5 mg/kg) or MK-801 (<0.16 mg/kg). The impact of these NMDAr antagonists on neocortical gamma oscillations was also investigated in 24 anesthetized rats, including control experiments with substances that modulate dopaminergic neurotransmission. The second part of this study investigated the relationship between the spontaneously occurring gamma oscillations in the electrocorticogram of the neocortex and the quantitative measures of locomotor activity in eight freely moving non-epileptic control (NEC) rats and seven Genetic Absence Epilepsy Rats from Strasbourg (GAERS) before and after subcutaneous administration of a single dose of ketamine (<5.0 mg/kg), MK-801 (<0.16 mg/kg) or vehicle (sodium chloride, .9%). / RESULTS: NMDAr antagonists, ketamine and MK-801 were found to both induce highly correlated dose dependant hyperlocomotion and aberrant gamma oscillations, with the time course of this more prolonged in following MK-801. Ketamine and MK-801 also induced significant increase in the gamma power in deep urethane anaesthetized and neuroleptanagesized rats, and slight increase in the gamma power in pentobarbital anaesthetized rats. In the second part of the study the power of spontaneously occurring electroencephalic gamma frequency oscillations were demonstrated to be significantly increased (twofold) in GAERS compared to their non-epileptic counterparts (NEC). At the onset of the epileptiform spike-and-wave discharges (seizures) there was a dramatic increase (seven to nine fold) compared to interictal gamma power. The administration of the NMDAr antagonists induced dose-dependent highly correlated aberrant interictal gamma oscillations and hyperlocomotion in GAERS similar to that seen in the non-epileptic rates except that peak and total locomotor responses were siginificantely decreased in GAERS following ketamine administration and that GAERS had a later peak in gamma power and in hyperlocomotion compared to NEC rats following MK-801 administration. / CONCLUSIONS: The present study demonstrated that ketamine and MK-801 dose-dependently induced highly correlated hyperlocomotion and aberrant gamma oscillations in non-epileptic control rats, suggesting that abnormal increased synchronization in ongoing gamma oscillations in cortical-related networks might cause dysfunctions of conscious integration, as seen in patients with schizophrenia. The study also demonstrated that ketamine- and MK-801-induced gamma hyperactivity is not caused by ataxic behavior and hyperlocomotion and is independent on conscious sensorimotor processing. Ketamine and MK-801 also induced similar changes in gamma power in rats with geneticly epileptic rats (GAERS), however this occurred of a baseline of approximately double the gamma power of the non-epileptic rats. This later finding suggests that gamma suggests that frequency oscillations might have a role in process of epileptogenesis. Overall the study results support the exciting possibility that aberrant gamma oscillations are a promising potential endophenotype for schizophrenia and epilepsy that could be used in the development of novel therapies for these two complex brain disorders.
| Identifer | oai:union.ndltd.org:ADTP/244985 |
| Date | January 2008 |
| Creators | Hakami, Tahir Mohammed Hadi Brohi |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Restricted Access: Abstract and Citation Only Available |
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