Basic Clin Neurosci

[Filomeno Robles]

ProfessorThuret and Professor Giese are co-leading the department to provide the best possible environment for world-class fundamental and clinical research in neurodegeneration and mechanisms of mental health while they strive to promote a culture of collaboration, research integrity, respect and inclusivity amongst members of the fundamental and clinical neuroscience community.

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The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.

Our knowledge of the neurobiology of schizophrenia, while still rudimentary, has advanced considerably in recent years. However, these findings have not translated to better treatments for those with schizophrenia. The three primary symptom groups, positive, cognitive and negative (Box 1), have been associated with reports of abnormalities in virtually every neurotransmitter system1,2,3,4,5. The onset of psychotic symptoms, which is strongly associated with alterations in dopamine function, is a key feature underpinning a clinical diagnosis6, 7. However, results from clinical research regarding the specific loci of dopamine dysfunction in schizophrenia8,9,10, have triggered a reappraisal of our perspective on the neurobiology of schizophrenia. Currently there is a disparity between the tests for positive symptoms in animal models and recent clinical evidence for dopaminergic abnormalities in schizophrenia. Therefore, it is critical that this contemporary clinical knowledge actively influences the agenda in applied basic neuroscience.

It is widely acknowledged that we cannot recreate the complicated symptom profile of schizophrenia in animal models. However, animal models (the majority and focus of the present article being rodent models) provide an avenue to invasively explore the role of neurotransmitters and circuitry in psychiatric diseases. To improve the poor predictive validity of treatments in animal models11, it is critical that our understanding and the use of animal models evolves alongside our knowledge of schizophrenia neurobiology. The delayed incorporation of new clinical findings to develop better animal models highlights the need for better communication between clinical and basic research communities.

In this article, we discuss the challenges clinicians and researchers are facing in understanding the neurobiology of positive symptoms and psychosis in schizophrenia. We discuss the implications this has for current assessments of positive symptoms in rodents and propose a more relevant set of tests for future study. Finally, the need for a joint focus on bi-directional translation between clinical and basic research is outlined.

An appreciation for the neuroanatomical differences in subcortical dopaminergic projections/circuitry between rodents and primates is essential for effective communication between clinical and basic researchers. For example, primates feature a more prominent substantia nigra and less distinctive ventral tegmental area than rodents. However, more pertinent to the current review are homologous functional subdivisions of the striatum observed in both rodents and primates21,22,23,24. These include the limbic, associative and sensorimotor areas (Fig. 1). The associative striatum, defined by its dense connectivity from the frontal and parietal associative cortices, is key for goal-directed action and behavioural flexibility. The limbic striatum, defined by connectivity to the hippocampus, amygdala and medial orbitofrontal cortex, is involved in reward and motivation. The sensorimotor striatum, defined by connectivity to sensory and motor cortices, is critical for habit formation. These functional subdivisions are also interconnected by feedforward striato-nigro-striatal projections25. The heavy basis on behavioural outcomes in neuropsychiatry has made functional subdivisions such as these more relevant than ever.

Midbrain dopamine neurons are the source of dopamine projections to the striatum in primates (left) and rodents (right). Important neuroanatomical differences exist, especially when considering functional subdivisions of the striatum. In the primate, the limbic system (orange) originates in the dorsal tier of the substantia nigra (the ventral tegmental area equivalent). In the rodent, the limbic system originates in ventral tegmental area, which sits medially to the substantia nigra. The midbrain projections to the associative striatum (yellow) and sensorimotor striatum (blue) follow a dorsomedial-to-ventrolateral topology

In healthy individuals, dopamine stimulants such as amphetamine can induce psychotic symptoms26, 27 and people with schizophrenia are more sensitive to these effects27, 28. Studies using positron emission tomography (PET) imaging have shown patients with schizophrenia show increases in subcortical synaptic dopamine content29, 30, abnormally high dopamine release after amphetamine treatment30,31,32,33,34,35 and increased basal dopamine synthesis capacity (determined indirectly by increased radiolabelled L-DOPA uptake)19,36, 37 compared with healthy controls. Increased subcortical dopamine synthesis and release capacity are strongly associated with positive symptoms in patients33, 38, and increased subcortical synaptic dopamine content is predictive of a positive treatment response29. It was widely anticipated that the limbic striatum would be confirmed as the subdivision where these alterations in dopamine function would be localised in patients. The basis for this prediction was the belief that reward systems were aberrant in schizophrenia39. However, as PET imaging resolution improved it was found that increases in synaptic dopamine content9, 10 and synthesis capacity8 were localised, or more pronounced37, in the associative striatum (Fig. 1; yellow). Furthermore, alterations in dopamine function within the associative striatum likely contribute to the misappropriate attribution of salience to certain stimuli, a key aspect of delusions and psychosis40.

Clinical studies have confirmed that dopamine abnormalities are also present prior to the onset of psychosis in schizophrenia and thus are not a consequence of psychotic episodes or antipsychotic exposure. Similar to what has been observed in patients with schizophrenia, ultra-high risk (UHR) subjects show increased subcortical synaptic dopamine content41 and basal dopamine synthesis capacity8, 42,43,44. Importantly, alterations in dopamine synthesis capacity in UHR subjects progress over time45 and are greater in subjects who transition to psychosis compared with those who do not46. Furthermore, higher baseline synaptic dopamine levels in UHR subjects predicts a greater reduction in positive symptoms after dopamine depletion41. Overall, these findings in UHR subjects are congruent with those observed in schizophrenia and provide evidence indicating that presynaptic dopaminergic abnormalities are present prior to the onset of psychosis.

Several avenues have been proposed to explain a selective increase in associative striatal dopamine function, such as alterations in hippocampal control of dopamine projections47, 48, alterations in cortical inputs to midbrain dopamine systems2, 49 and, although little direct evidence has been observed, developmental alterations in dopamine neurons themselves50, 51. Furthermore, other pathways and/or neurotransmitters may be more critical in treatment-resistant patients52. We propose a network model whereby dysfunction in a central circuit, including the associative striatum, prefrontal cortex and thalamus, is critical for the expression of psychotic symptoms in schizophrenia. This model would suggest that dysfunction in auxiliary circuits (both limbic and cortical) contribute to psychotic symptoms by feeding into this primary network. Ascertaining the role of dopaminergic dysfunction, in the context of networks important for psychotic symptoms in schizophrenia, will provide a better base for constructing objective readouts in basic and clinical research.

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