Impaired GluN2A NMDAR function, aberrant salience and maladaptive learning in schizophrenia

Schizophrenia is a common psychiatric disorder which has profound effects on individual patients and high economic costs for society. Current treatments have only limited efficacy. Recent evidence from genetic studies of schizophrenia has converged on the GRIN2A gene, which codes for the GluN2A subunit of the NMDA receptor (NMDAR) subtype of glutamate receptor, as a key target in the disease. However, how GluN2A dysfunction impacts on the neurobiological and psychological processes that malfunction in schizophrenia remains unknown. A popular idea is that certain schizophrenic symptoms, such as delusions, reflect learning the wrong things about the world and hence the formation of abnormal or inappropriate memories. The reasons why this occurs are not clear, but one possibility is that it happens when too much attention is paid to particular stimuli in the environment, such that these stimuli take on excessive significance and become inappropriately linked to other things. These stimuli are said to have acquired “aberrant salience” and it is generally considered that this reflects increased levels of the neurotransmitter dopamine. This is potentially consistent with the fact that most anti-psychotic drugs, which are used to treat disorders like schizophrenia, work by blocking dopamine receptors. Dopamine levels in the brain increase in response to novel or surprising stimuli, and are important for learning associations between events. So does GluN2A dysfunction cause aberrant salience and increased dopamine in the brain and, if so, how? We will now test the hypothesis that GluN2A NMDAR dysfunction causes aberrant salience and increased dopamine as a result of deficits in short-term habituation. NMDARs are important for synaptic plasticity and there is an increasingly popular viewpoint that impaired synaptic plasticity might be an important cause of schizophrenia. Importantly, we have recently shown that (i) genetically modified mice with impaired synaptic plasticity and (ii) normal mice given a drug which blocks NMDARs, exhibit deficits in short-term habituation. Habituation allows us to reduce attention to unimportant stimuli that we have already experienced. Thus, habituation deficits result in too much attention being paid to inconsequential stimuli (i.e. aberrant salience). Furthermore, mice with impaired synaptic plasticity also exhibit increased levels of dopamine in the striatum, as a direct consequence of deficits in short-term habituation and stimuli remaining “as if novel” for longer. Attending too much to irrelevant stimuli can lead to learning the wrong things about the world and hence to abnormal memories. Given our recent findings, we predict that GluN2A deficient mice will: have deficits in short-term habituation leading to aberrant salience, exhibit increased levels of striatal dopamine as a direct consequence of impaired short-term habituation, that this will result in the formation of maladaptive and inappropriate associations between cues in the environment, and that this could be dependent on increased dopamine signaling. We will test these hypotheses in genetically modified mice lacking GluN2A or with reduced GluN2A function following removal of the protein C-terminal domain (which is especially linked to schizophrenia). In this way we will establish the mechanisms though which GluN2A dysfunction leads to maladaptive learning, and how this might drive not only psychotic symptoms like delusions, but also cognitive symptoms. Cognitive symptoms are key predictors of long-term functional outcomes in patients but are poorly targeted by current treatments. Thus, understanding GluN2A dysfunction will have novel therapeutic implications.