![]() The glutamate system is a prime candidate for this upstream abnormality 6, 11, 12, 13, 14, 15 with diverse evidence for glutamatergic dysfunction, particularly NMDAR signalling, in the pathophysiology of schizophrenia, 16, 17 including data from postmortem, 18, 19 neuroimaging, 20, 21 and immunological 22 studies of the disorder, as well as indirectly from pharmacological findings 17 and animal models. Howes and Kapur 8 noted that although the dysregulated, hyperdopaminergic state could be the result of a primary abnormality in the mesolimbic dopamine system, it could also be a secondary consequence of some other brain disturbance (or disturbances) and thus represent a ‘final common pathway’ in schizophrenia. 8, 10 Indeed, while considerable effort has gone into investigating and describing the putative links between dopamine, aberrant salience and psychosis, comparatively little effort has been expended in identifying the possible causes of aberrant salience. 6, 7, 8, 9 However, the cause of this dopamine dysregulation is unspecified in Kapur’s model and has not yet been resolved. 1, 2, 3 Dopaminergic abnormalities have a similarly proximate role in aberrant salience, 4, 5 which Kapur and others have theorized is central to the genesis and understanding of positive psychotic symptoms. There is now strong evidence that hyper-dopaminergic activity underlies the positive psychotic symptoms of schizophrenia. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as ‘models of schizophrenia’ but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms. As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). ![]() We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). ![]() These mice show deficits in short-term habituation. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. ![]()
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