K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration

Schiemann, Julia; Schlaudraff, Falk; Klose, V.; Bingmer, Markus; Seino, Susumu; Magill, Peter J.; Zaghloul, Kareem A.; Schneider, Gerd‐Helge; Liss, Birgit; Roeper, Jochen

doi:10.1038/nn.3185

Cited by 195 publications

(188 citation statements)

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“…For example, a burst-firing mode has been shown to be sufficient for behavioral conditioning (conditioned place preference) (73) and to be necessary for learning of cue-dependent learning tasks (53). Furthermore, reward-related stimuli presentation (74) and food restriction (75) correlate with burst-firing increase, and burst firing in a subset of SNc neurons mediates noveltyinduced exploration (76).…”

Section: Discussionmentioning

confidence: 99%

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Pristerà

Lin

Kaufmann

et al. 2015

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

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Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by L-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice.FOXA1 | FOXA2 | dopamine | burst firing | feeding M ost dopaminergic (DAergic) neurons in the adult midbrain are grouped in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). VTA and SNc neurons have been classically linked to diverse functions and different projection targets (1). VTA neurons project to the ventral striatum, cortical areas, and limbic structures. Midbrain dopaminergic (mDA) neurons in this group are implicated in emotional behavior, motivational functions, and reward mechanisms (2-4). On the other hand, SNc neurons mainly project to the dorsal striatum and regulate motor function (5). mDA neurons are of major interest in biomedical research because degeneration of SNc mDA neurons is the hallmark of Parkinson's disease (6). In addition, mDA neuron dysfunction is associated with cognitive impairment, motivational deficits, addiction, and drug abuse (7-10). The identification of factors that maintain dopamine (DA) function in developed adult neurons may contribute to the understanding of the mechanisms supporting the homeostasis of mDA neurons and therefore help in identifying therapeutic targets to treat disorders arising from dysfunctional mDA neurons.FOXA1 and FOXA2 (FOXA1/2) are members of the wingedhelix/forkhead transcription factors, which share over 95% homology between mice and humans (11). FOXA1/2 are so-called "pioneer proteins" that, by binding to tightly condensed chromatin in promoters and enhancer regions, facilitate access of other transcription factors (12, 13). FOXA1/2 regulate the development of diverse organs, including the lung, liver, pancreas, prostate, and kidneys (14). We have also found that FOXA1/2 play a crucial role in the generation of mDA neurons during early and late development, regulating both their specification and dif...

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Section: Discussionmentioning

confidence: 99%

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Pristerà

Lin

Kaufmann

et al. 2015

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

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“…Aside from ␤-cells, neurons in the central nervous system involved in a wide range of physiological and pathological processes, including energy homeostasis (18,(61)(62)(63), epilepsy (64,65), and Parkinson disease (66), express K ATP channels and are subjected to regulation by leptin and metabolic signals. Thus, the K ATP channel regulatory mechanism identified here may extend well beyond pancreatic ␤-cells, with broad implications in metabolic regulation in health and disease.…”

Section: Discussionmentioning

confidence: 99%

Leptin Regulates KATP Channel Trafficking in Pancreatic β-Cells by a Signaling Mechanism Involving AMP-activated Protein Kinase (AMPK) and cAMP-dependent Protein Kinase (PKA)

Chen

Kryukova

Shyng

2013

Journal of Biological Chemistry

105

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Background: Leptin inhibits insulin secretion by increasing ␤-cell K ATP currents. Results: Leptin causes a transient increase in surface K ATP channel density. This increase is dependent on AMPK and PKA and actin depolymerization. Conclusion: Leptin increases K ATP currents by recruiting K ATP channels to the ␤-cell membrane. Significance: K ATP channel trafficking is an important physiological mechanism to regulate channel activity.

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“…In vivo extracellular single-unit recordings and juxtacellular labeling were essentially as described previously (52). In brief, single units of DA VTA and DA SN neurons were extracellularly recorded in isoflurane-anesthetized mice.…”

Section: Methodsmentioning

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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K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration

Cited by 195 publications

References 56 publications

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Leptin Regulates KATP Channel Trafficking in Pancreatic β-Cells by a Signaling Mechanism Involving AMP-activated Protein Kinase (AMPK) and cAMP-dependent Protein Kinase (PKA)

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

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