Negative Symptoms of Schizophrenia and Dopaminergic Transmission: Translational Models and Perspectives Opened by iPSC Techniques

Abstract

Negative symptoms (NS) represent a heterogeneous dimension of schizophrenia (SCZ), associated with a poor functional outcome. A dysregulated dopamine (DA) system, including a reduced D1 receptor activation in the prefrontal cortex, DA hypoactivity in the caudate and alterations in D3 receptor activity, seems to contribute to the pathogenesis of NS. However, failure to take into account the NS heterogeneity has slowed down progress in research on their neurobiological correlates and discoveries of new effective treatments. A better neurobiological characterization of NS is needed, and this requires objective quantification of their features that can be applied in translational models, such as animal models and human inducible pluripotent stem cells (iPSC). In this review we summarize the evidence for dopaminergic alterations relevant to NS in translational animal models focusing on dysfunctional motivation, a core aspect of NS. Among others, experiments on mutant rodents with an overexpression of DA D2 or D3 receptors and the dopamine deficient mice are discussed. In the second part we summarize the findings from recent studies using iPSC to model the pathogenesis of SCZ. By retaining the genetic background of risk genetic variants, iPSC offer the possibility to study the effect of de novo mutations or inherited polymorphisms from subgroups of patients and their response to drugs, adding an important tool for personalized psychiatry. Given the key role of DA in NS, we focus on findings of iPSC-derived DA neurons. Since implementation of iPSC-derived neurons to study the neurobiology of SCZ is a relatively recent acquisition, the available data are limited. We highlight some methodological aspects of relevance in the interpretation of in vitro testing results, including limitations and strengths, offering a critical viewpoint for the implementation of future pharmacological studies aimed to the discovery and characterization of novel treatments for NS.

Trends in big data analyses by multicenter collaborative translational research in psychiatry

“…Although many SZ studies with iPSC technology have been published, 162 there are a few pharmacological studies using iPSC‐derived neurons from patients with SZ. 163 Recently, a pair of monozygotic twins with treatment‐resistant SZ and discordant responses to clozapine, a drug for treatment‐resistant SZ, was recruited by COCORO. Monozygotic twins with treatment‐resistant SZ and discordant responses to clozapine are extremely rare.…”

Advantages and Limitations of Animal Schizophrenia Models

“…Negative symptoms of the illness may be modeled by inducing frontal hypodopaminergic effect, which is representative of schizophrenia symptoms, such as poor motivation [ 25 ], as people diagnosed with schizophrenia show a tendency to make decisions linked to lower effort [ 26 ]. Injection of 6-OHDA into rats’ mPFC leads to increased DA levels in striatum and nucleus accumbens [ 27 ], which points to the theory of increased DA signaling in subcortical regions and diminished one in frontal parts of the brain in schizophrenic subjects [ 28 ].…”

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

“…In SCZ, the dopaminergic hypothesis is supported by the effectiveness of all known antipsychotic drugs in alleviating the positive symptoms of SCZ by blocking striatal dopamine D2 receptors [202,203,208]. More recent studies based on genetic animal models with dysregulated dopaminergic neurotransmission [209] and pharmacological approaches in patients have demonstrated hyperexcitability and deficits in sensory gating that overlap with the behavioral deficits of SCZ and BIP patients [210].…”