Glutamatergic dysfunction as a cause of aberrant salience.

Although we have known for many years that schizophrenia has a strong genetic component, recent large scale genome-wide association studies (GWAS) represent a landmark discovery by identifying which genes predispose to the disorder. However, this is just a starting point. The challenge for experimental neuroscientists is now to determine how these genes impact on the neurobiological and psychological processes that likely malfunction in schizophrenia.

Considerable evidence argues that dysfunction in the glutamate system is an important contributory factor in schizophrenia. Although several glutamate-related genes and their protein products have been linked to schizophrenia, the GluA1 subunit of the AMPAR and the GluN2A NMDAR subunit (both of which were implicated in recent GWAS), are two of the best understood in terms of function. They therefore represent important exemplars which we will use in the following program of work.

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 might occur 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.

We have shown previously that genetically modified mice lacking either GluA1 or GluN2A glutamate receptor subunits exhibit selective deficits in a short-lasting form of habituation. Habituation allows us to reduce attention to unimportant stimuli that we have already experienced, thus allowing us to allocate our attentional resources to relevant stimuli in our world instead. Habituation deficits result in too much attention being paid to a stimulus. Attending too much to an irrelevant stimulus can lead to learning the wrong things about the world and hence to abnormal memories. Thus, we have hypothesised that glutamatergic dysfunction, leading to deficits in short-term habituation to recently experienced stimuli, might be an important cause of aberrant salience and increased dopamine signals in the brain.

The aim of this proposal is to test this hypothesis. To do this we will record dopamine signals in real time in the striatum of GluA1 and GluN2A knockout mice, using a technique called fast-scan cyclic voltammetry. These recordings will be made in freely moving mice in response to neutral light stimuli. When the same light is presented twice in quick succession (with a 30 sec interval), normal animals habituate to the light and pay less attention on its second presentation. We will determine whether habituation deficits caused by glutamate dysfunction lead to increased dopamine signals in the brain. Furthermore, we will investigate the neural circuits that might underlie these changes and, in particular, the role of the hippocampus and hippocampal glutamate receptors. Finally, we will look at the downstream consequences of these changes in attention. Dopamine signals in the striatum exhibit a well characterized profile during associative learning (they are large to novel or surprising events and small to well-predicted events). We will investigate how glutamatergic dysfunction and deficits in short-term habituation influence these dopamine signal changes.

If deficits in short-term habituation cause aberrant salience and elevated dopamine, then identifying mechanisms that support short-term habituation, and their underlying neural circuits, may have novel therapeutic implications.

Psychosis is a key feature of schizophrenia and several other neuropsychiatric disorders. Current thinking suggests that psychosis is a disorder of aberrant salience. Salience comprises the ability of a stimulus to grab attention and drive action. Aberrant salience describes when a stimulus continues to grab inappropriately high levels of attention, and is likely mediated via elevated dopamine. However, the causes of this dopamine dysregulation are unknown. We propose that it may be a consequence of glutamatergic dysfunction, which is strongly implicated in the aetiology of schizophrenia. For example, the GluA1-AMPA and GluN2A-NMDA glutamate receptor subunit loci are now genome-wide significant for schizophrenia. Notably, genetically modified mice that lack these genes exhibit deficits in short-term habituation, such that they continue to pay inappropriately high levels of attention to recently presented stimuli. We hypothesise that these deficits in short-term habituation could be a mediator of aberrant salience and elevated dopamine signals, leading to psychosis.

We will test this hypothesis empirically by recording phasic dopamine transients in real time in the striatum of genetically modified mice that lack GluA1 or GluN2A, using fast-scan cyclic voltammetry. Recordings will be made in freely moving mice in response to recently presented neutral stimuli. Moreover, we will investigate the neural circuits that might lead to these hyper-dopaminergic responses and, in particular, the role of the hippocampus and hippocampal glutamate receptors. Finally, we will also look at the downstream consequences of these changes in attention, and how they affect dopamine prediction error signals during associative learning. The work will advance understanding of glutamate-dopamine links in psychosis, and the basis of aberrant salience, as well as having novel therapeutic implications.

Who will benefit?

In addition to the academic community (see Academic Beneficiaries), the other main potential beneficiaries of our work will be the pharmaceutical industry, clinicians, and ultimately patients and carers.

How will they benefit?

The aim of this proposal is to test the hypothesis that deficits in short-term habituation, resulting from glutamatergic dysfunction, are a primary cause of aberrant salience and elevated dopamine, which can lead to psychosis in disorders like schizophrenia. If our hypothesis is correct then establishing the neural circuits and mechanisms that underlie short-term habituation, and identifying why they then go wrong in disorders like schizophrenia, could identify novel treatment strategies for preventing or alleviating psychosis. Given that current anti-psychotic drugs, which act by blocking dopamine receptors, can manage patients' behaviour but don't fix the underlying problem(s), then developing novel therapies is likely to be of great importance. This includes psychosis in dementia, for which existing anti-psychotic medications are poorly tolerated and guidelines strongly discourage their use. As drug treatments are developed that slow down or even halt the progressive nature of Alzheimer's Disease, there is going to be an ever-increasing need to develop additional treatments for symptomatic relief for aspects of the disorder like psychosis.

Ultimately, the development of novel treatment strategies and therapies for psychosis will produce both economic and societal benefits, with the endpoint of improving human health. By the end of this grant we will know whether short-term habituation deficits arising from glutamatergic dysfunction are a cause of aberrant salience and elevated dopamine signals. A next step would be to test the prediction that short-term habituation deficits arising from non-glutamatergic dysfunction would also lead to elevated dopamine signals. If our hypothesis is proved correct then we will be in a position to move forward and identify the neural circuits and mechanisms that support short-term habituation and why they go wrong in disorders like schizophrenia. We suggest that this is the kind of basic systems neuroscience which is now needed to span the gap between descriptive phenomenology and the fundamental, but hard to interpret, genetic advances.