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Title: Characterising mismatch negativity biomarker signatures in preclinical models relevant to schizophrenia
Author: O'Reilly, Jamie Alexander
ISNI:       0000 0004 6423 1203
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2017
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Mismatch negativity (MMN) has been hailed as a 'break-through biomarker in predicting psychosis onset' (Naatanen 2015). This is because deficits have been found in clinical populations diagnosed with psychotic syndromes such as schizophrenia. MMN is an auditory evoked potential (AEP) difference waveform produced by subtracting standard from deviant stimuli AEPs elicited by an oddball paradigm; purportedly arising from any discriminable change in auditory stimulation. Despite nearly four decades of basic research into MMN the underlying mechanisms are not fully understood. Although popular theories suggest that it reflects a sensory-memory trace disruption and/or differential adaptation of responses to standard and deviant/oddball stimuli, there remains considerable debate over the neural mechanism and its interpretation. Nevertheless, associations made between N-methyl-d-aspartate (NMDA) receptors in schizophrenia and findings showing that NMDA receptor antagonists (e.g. ketamine) induce MMN deficits in healthy volunteers suggests abnormal MMNs share common traits and support its use as a biomarker from an electrophysiological perspective. However, this is still speculative and there is great impetus on developing reliable preclinical models of MMN in order to examine the underpinning neurophysiology and therefore its reliance on NMDA receptors as a test of pathology in schizophrenia. A question this thesis aims to address is whether a mismatch response (MMR) exists in rodents which is analogous to the human MMN, and whether its modification by NMDA receptor antagonists or as a result of schizophrenia-related genetic modification sheds light on its utility as a biomarker in disease models of schizophrenia. This thesis describes three experiments performed using mitogen activated protein kinase kinase 7 heterozygous (Map2k7+/-ˆ’) mice and their wild-type littermates, incorporating NMDA receptor antagonism with ketamine (10 mg/kg i.p.). The MAP2K7 gene is associated with schizophrenia and codes for a post-synaptic intracellular signalling enzyme which is activated following glutamatergic excitation, for instance via NMDA receptors. The MMR to stimuli duration, frequency and intensity changes in oddball paradigms are characterised in urethane-anaesthetised and conscious animals, followed by an examination of laminar auditory cortex activity in response to these physical changes. Data recorded throughout this series of experiments includes cortical electroencephalography (EEG), video footage, and intra-cortical spiking information. These data were then analysed using various time, frequency and time-frequency domain techniques; although mainly focussing on the event-related potential (ERP) approach. Recordings demonstrated substantial differences in the AEP waveform evoked from urethane-anaesthetised and conscious animals, with the latter displaying considerably more dynamic responses, although onset and offset of auditory stimuli induced comparable waveform features in both states. Effects of varying physical properties of stimuli in oddball and control paradigms have been identified as key determinants of the AEP and correspondingly the MMR difference waveform amplitudes. The finding that NMDA receptor disruption in conscious animals by ketamine acutely diminishes a specific AEP feature (≈20-50 ms post stimulus onset) which may impact the resulting MMR tentatively links this study in mice with findings from humans noted above. Ketamine was also found to enhance animal movement and increase EEG spectral power in the 50-70 Hz (gamma-band) frequency range, observed for approximately 10 minutes following drug administration. Both anaesthetised and conscious cohorts of Map2k7+/-’ mice displayed a significantly enhanced onset response (≈0-20 ms) in the AEP. Interestingly, ketamine did not appear to have a differential effect on Map2k7+/-ˆ’ mice compared with the wild-type group, suggesting that NMDA receptor-mediated neurotransmission is unimpaired in this genetic model relevant to schizophrenia. Overall, the findings suggest that the MMR in mice is fundamentally influenced by the physical properties of stimuli employed; ketamine causes an acute, specific alteration to the AEP in conscious mice in addition to other electrophysiological and behavioural changes; and Map2k7 gene disruption causes a specific and replicable change in AEP amplitude. Overall this study indicates that mouse models are useful for exploring the effects of different pharmacological and genetic manipulations on the auditory evoked response; however, MMN data in clinical cohorts still needs to be interpreted with care. In order to address whether the rodent MMR is analogous to human MMN, it would be necessary to probe how influencing factors revealed in the rodent studies impact on the human response. Whilst the rodent MMR and human MMN show some degree of translation, their potential as schizophrenia biomarkers requires further characterisation and validation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Eng.D.) Qualification Level: Doctoral