D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex

Li, Yanchun; Kellendonk, Christoph; Simpson, Eleanor H.; Kandel, Eric R.; Gao, Wen-Jun

doi:10.1073/pnas.1109718108

Cited by 74 publications

(63 citation statements)

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“…Recent studies have shown that reversible overexpression of D2 receptors in the striatum of mice generates cognitive deficits, particularly in working memory (45,46). The authors reported that increased striatal D2 receptor function leads to a reduced prefrontal cortex (PFC) dopaminergic modulation of GABAergic inhibitory neurotransmission associated with impaired working memory.…”

Section: Discussionmentioning

confidence: 99%

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs¹,

Snyder²,

Jacobsen³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)-and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA-or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β was deleted in either DA D1-or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3β in D2 (D2GSK3β −/− ) but not D1 (D1GSK3β −/− ) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β −/− or D1GSK3β −/− mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3β, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β −/− or D1GSK3β −/− mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be β-arrestin2-and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.functional selectivity | schizophrenia | bipolar disorder | striatum | frontal cortex

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Section: Discussionmentioning

confidence: 99%

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Urs¹,

Snyder²,

Jacobsen³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Specifically, striatal D2R overexpression results in increased levels of DA, decreased DA turnover, and increased D1 receptor activation in PFC. In addition, more recent results suggest that striatal D2R overexpression may produce a deficit in inhibitory transmission in the PFC, leading to a state of cortical hyperactivity (Li et al, 2011). Given the critical importance of the balance of cortical excitatory and inhibitory transmission for information processing and cognitive flexibility (Yizhar et al, 2011), including sensitivity to the value of response options associated with future rewards (Gruber et al, 2010), this imbalance may play a critical role in the behavioral deficits reported here.…”

Section: D2r Overexpression Produces a Deficit In Willingness To Workmentioning

confidence: 94%

Dissociation of Hedonic Reaction to Reward and Incentive Motivation in an Animal Model of the Negative Symptoms of Schizophrenia

Ward

Simpson

Richards

et al. 2012

Neuropsychopharmacol

127

118

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We previously showed that mice that selectively and reversibly overexpress striatal D2 receptors (D2R-OE) model the negative symptoms of schizophrenia. Specifically, D2R-OE mice display a deficit in incentive motivation. The present studies investigated the basis for this deficit. First, we assessed whether hedonic reaction to reward is intact in D2R-OE mice. We assessed licking behavior and videoscored positive hedonic facial reactions to increasing concentrations of sucrose in control and D2R-OE mice. We found no difference between D2R-OE mice and controls in hedonic reactions. To further understand the basis of the motivational deficit, mice were given a choice between pressing a lever for access to a preferred reward (evaporated milk) or consuming a freely available less preferred reward (home-cage chow). D2R-OE mice pressed less for the preferred milk and consumed more of the freely available less preferred chow, indicating that striatal overexpression of postsynaptic D2Rs can alter cost/benefit computations, leading to a motivational deficit. This motivational impairment was ameliorated when the transgene was turned off and D2R levels were normalized. Such a deficit may arise from impaired ability to represent the value of future rewards. To test this, we used operant concurrent schedules and found reduced sensitivity to the value of future outcomes in D2R-OE mice. These results demonstrate for the first time in a transgenic animal model of schizophrenia a dissociation between hedonic reaction to reward and incentive motivation, and show a striking parallel to the proposed neurobiological and psychological mechanisms of impaired incentive motivation in schizophrenia. Neuropsychopharmacology (2012Neuropsychopharmacology ( ) 37, 1699Neuropsychopharmacology ( -1707 doi:10.1038/npp.2012 published online 14 March 2012 Keywords: hedonia; incentive motivation; operant; D2 receptor overexpression; schizophrenia; mouse models INTRODUCTIONMotivational deficits in schizophrenia are of particular clinical significance, as they greatly impair the overall functioning and quality of life of patients and do not respond well to current medications. Reduced motivation could result from anhedonia, an inability to experience pleasure from events or stimuli that others find pleasurable, or avolition, a deficit in the initiation or maintenance of goal-directed behavior. Surprisingly, given the intuitive relation between hedonia and motivation, recent findings from several research groups indicate a dissociation between hedonic reaction to rewarding stimuli and motivated behavior in patients with schizophrenia (Cohen and Minor, 2010;Gard et al, 2007;Heerey and Gold, 2007). Although there are counterexamples , the majority of the current literature shows relatively intact subjective hedonic reaction to rewarding stimuli, but impaired incentive motivation.Although the molecular underpinnings of impaired incentive motivation in schizophrenia are not precisely known, animal research points to distinct neurobiological substrates u...

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“…D2R-OE mice also exhibit phenotypes similar to the negative symptoms of schizophrenia: a deficit in incentive motivation, without disruption of hedonic processes (13,(15)(16)(17). We previously reported that these behavioral deficits in striatal D2R-OE mice are accompanied by changes in cortical DA function (11,18). D2R overexpression restricted to the striatum led to alterations in DA function in the PFC.…”

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confidence: 99%

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Krabbe

Duda

Schiemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.ventral tegmental area | dopamine D2 receptor | burst activity | NMDA receptor | schizophrenia D eficits in cognition and motivation are core features of schizophrenia (1, 2). These symptoms are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as a diagnostic criterion for schizophrenia spectrum disorder (3) and have a significant impact on patients' overall functioning and quality of life (4, 5). Currently, there are no effective treatments for these disabling aspects of the disease. Therefore, a high priority in the study of schizophrenia is to increase our understanding of the neurobiology of cognitive and motivational deficits. The midbrain dopamine (DA) system affects cognition and motivation in healthy subjects. It includes DA neurons of the ventral tegmental area (VTA), projecting to prefrontal cortex (PFC) and limbic areas (e.g., ventral striatum), and DA neurons of the substantia nigra (SN), projecting to the dorsal striatum (6). Involvement of the midbrain DA system is strongly implicated in both the cognitive and motivational deficits observed in schizophrenia (7,8). Moreover, it is well documented that the DA system is altered in patients with schizophrenia (reviewed in refs. 9, 10).To model the increase in striatal DA D2 receptor (D2R) activity observed in patients with schizophrenia, we previously generated transgenic mice that selectively and reversibly overexpress D2Rs in the striatum (D2R-OE mice) (11). In this model, expression of the transgenic D2Rs is restricted to the postsy...

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D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex

Cited by 74 publications

References 39 publications

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Dissociation of Hedonic Reaction to Reward and Incentive Motivation in an Animal Model of the Negative Symptoms of Schizophrenia

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

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