Contact
Biomedical Research Center251 Bayview Boulevard
Suite 200
Baltimore, MD 21224
Email: stephanie.gantz@nih.gov
Education
Ph.D. - Vollum Institute at Oregon Health & Science University
Research Interests
Dr. Stephanie C. Gantz received her B.A. in Biology from Reed College in 2007. She obtained her Ph.D. in Neuroscience from the Vollum Institute at Oregon Health & Science University in 2015, under the mentorship of Dr. John Williams. Her dissertation research described spontaneous synaptic currents mediated by G protein-coupled dopamine D2 receptor activation of GIRK channels. After obtaining her degree, she trained as a postdoctoral fellow in Dr. Bruce Bean’s laboratory at Harvard Medical School. There, Dr. Gantz discovered that endocannabinoids, mobilized by Gq protein-coupled receptor activation, directly alter intrinsic excitability of dopamine neurons through lipid interactions. In October 2016, Dr. Gantz joined NIDA as a post-doctoral fellow where she continues her research on the influence of Gq protein-coupled receptor activation on membrane ion channels.
Selected Publications
2018
Francis, Tanner Chase; Gantz, Stephanie C; Moussawi, Khaled; Bonci, Antonello
Synaptic and intrinsic plasticity in the ventral tegmental area after chronic cocaine. Journal Article
In: Curr Opin Neurobiol, vol. 54, pp. 66–72, 2018, ISSN: 1873-6882 (Electronic); 0959-4388 (Linking).
@article{Francis:2018aa,
title = {Synaptic and intrinsic plasticity in the ventral tegmental area after chronic cocaine.},
author = {Tanner Chase Francis and Stephanie C Gantz and Khaled Moussawi and Antonello Bonci},
url = {https://www.ncbi.nlm.nih.gov/pubmed/30237117},
doi = {10.1016/j.conb.2018.08.013},
issn = {1873-6882 (Electronic); 0959-4388 (Linking)},
year = {2018},
date = {2018-09-17},
journal = {Curr Opin Neurobiol},
volume = {54},
pages = {66--72},
address = {Intramural Research Program, Synaptic Plasticity Section, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, MD 21224, USA.},
abstract = {Cocaine exposure induces persistent changes in synaptic transmission and intrinsic properties of ventral tegmental area (VTA) dopamine neurons. Despite significant progress in understanding cocaine-induced plasticity, an effective treatment of cocaine addiction is lacking. Chronic cocaine potentiates excitatory and alters inhibitory transmission to dopamine neurons, induces dopamine neuron hyperexcitability, and reduces dopamine release in projection areas. Understanding how intrinsic and synaptic plasticity interact to control dopamine neuron firing and dopamine release could prove useful in the development of new therapeutics. In this review, we examine recent literature discussing cocaine-induced plasticity in the VTA and highlight potential therapeutic interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cocaine exposure induces persistent changes in synaptic transmission and intrinsic properties of ventral tegmental area (VTA) dopamine neurons. Despite significant progress in understanding cocaine-induced plasticity, an effective treatment of cocaine addiction is lacking. Chronic cocaine potentiates excitatory and alters inhibitory transmission to dopamine neurons, induces dopamine neuron hyperexcitability, and reduces dopamine release in projection areas. Understanding how intrinsic and synaptic plasticity interact to control dopamine neuron firing and dopamine release could prove useful in the development of new therapeutics. In this review, we examine recent literature discussing cocaine-induced plasticity in the VTA and highlight potential therapeutic interventions.
Gantz, Stephanie C; Ford, Christopher P; Morikawa, Hitoshi; Williams, John T
The Evolving Understanding of Dopamine Neurons in the Substantia Nigra and Ventral Tegmental Area. Journal Article
In: Annu Rev Physiol, vol. 80, pp. 219–241, 2018, ISSN: 1545-1585 (Electronic); 0066-4278 (Linking).
@article{Gantz:2018aa,
title = {The Evolving Understanding of Dopamine Neurons in the Substantia Nigra and Ventral Tegmental Area.},
author = {Stephanie C Gantz and Christopher P Ford and Hitoshi Morikawa and John T Williams},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28938084},
doi = {10.1146/annurev-physiol-021317-121615},
issn = {1545-1585 (Electronic); 0066-4278 (Linking)},
year = {2018},
date = {2018-02-10},
journal = {Annu Rev Physiol},
volume = {80},
pages = {219--241},
address = {Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.},
abstract = {In recent years, the population of neurons in the ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that the projections, neurochemistry, and receptor and ion channel expression in this cell population vary widely. This review centers on the intrinsic properties and synaptic regulation that control the activity of dopamine neurons. Although all dopamine neurons fire action potentials in a pacemaker pattern in the absence of synaptic input, the intrinsic properties that underlie this activity differ considerably. Likewise, the transition into a burst/pause pattern results from combinations of intrinsic ion conductances, inhibitory and excitatory synaptic inputs that differ among this cell population. Finally, synaptic plasticity is a key regulator of the rate and pattern of activity in different groups of dopamine neurons. Through these fundamental properties, the activity of dopamine neurons is regulated and underlies the wide-ranging functions that have been attributed to dopamine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In recent years, the population of neurons in the ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that the projections, neurochemistry, and receptor and ion channel expression in this cell population vary widely. This review centers on the intrinsic properties and synaptic regulation that control the activity of dopamine neurons. Although all dopamine neurons fire action potentials in a pacemaker pattern in the absence of synaptic input, the intrinsic properties that underlie this activity differ considerably. Likewise, the transition into a burst/pause pattern results from combinations of intrinsic ion conductances, inhibitory and excitatory synaptic inputs that differ among this cell population. Finally, synaptic plasticity is a key regulator of the rate and pattern of activity in different groups of dopamine neurons. Through these fundamental properties, the activity of dopamine neurons is regulated and underlies the wide-ranging functions that have been attributed to dopamine.
2017
Gantz, Stephanie C; Bean, Bruce P
Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling. Journal Article
In: Neuron, vol. 93, no. 6, pp. 1375–1387, 2017, ISSN: 1097-4199 (Electronic); 0896-6273 (Linking).
@article{Gantz:2017aa,
title = {Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling.},
author = {Stephanie C Gantz and Bruce P Bean},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28262417},
doi = {10.1016/j.neuron.2017.02.025},
issn = {1097-4199 (Electronic); 0896-6273 (Linking)},
year = {2017},
date = {2017-03-22},
journal = {Neuron},
volume = {93},
number = {6},
pages = {1375--1387},
address = {Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: stephanie.gantz@nih.gov.},
abstract = {The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase alpha. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase alpha. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA.
2015
Gantz, Stephanie C; Robinson, Brooks G; Buck, David C; Bunzow, James R; Neve, Rachael L; Williams, John T; Neve, Kim A
Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium. Journal Article
In: Elife, vol. 4, 2015, ISSN: 2050-084X (Electronic); 2050-084X (Linking).
@article{Gantz:2015aa,
title = {Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium.},
author = {Stephanie C Gantz and Brooks G Robinson and David C Buck and James R Bunzow and Rachael L Neve and John T Williams and Kim A Neve},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26308580},
doi = {10.7554/eLife.09358},
issn = {2050-084X (Electronic); 2050-084X (Linking)},
year = {2015},
date = {2015-08-26},
journal = {Elife},
volume = {4},
address = {Vollum Institute, Oregon Health & Science University, Portland, United States.},
abstract = {D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.
Gantz, Stephanie C; Robinson, Brooks G; Buck, David C; Bunzow, James R; Neve, Rachael L; Williams, John T; Neve, Kim A
Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium. Journal Article
In: Elife, vol. 4, 2015, ISSN: 2050-084X (Electronic); 2050-084X (Linking).
@article{Gantz:2015aab,
title = {Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium.},
author = {Stephanie C Gantz and Brooks G Robinson and David C Buck and James R Bunzow and Rachael L Neve and John T Williams and Kim A Neve},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26308580},
doi = {10.7554/eLife.09358},
issn = {2050-084X (Electronic); 2050-084X (Linking)},
year = {2015},
date = {2015-08-26},
journal = {Elife},
volume = {4},
address = {Vollum Institute, Oregon Health & Science University, Portland, United States.},
abstract = {D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.
Gantz, Stephanie C; Levitt, Erica S; Llamosas, Nerea; Neve, Kim A; Williams, John T
Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA. Journal Article
In: Cell Rep, vol. 12, no. 6, pp. 944–954, 2015, ISSN: 2211-1247 (Electronic).
@article{Gantz:2015ab,
title = {Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA.},
author = {Stephanie C Gantz and Erica S Levitt and Nerea Llamosas and Kim A Neve and John T Williams},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26235617},
doi = {10.1016/j.celrep.2015.07.005},
issn = {2211-1247 (Electronic)},
year = {2015},
date = {2015-08-11},
journal = {Cell Rep},
volume = {12},
number = {6},
pages = {944--954},
address = {Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.},
abstract = {Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission.
2014
Mergy, Marc A; Gowrishankar, Raajaram; Gresch, Paul J; Gantz, Stephanie C; Williams, John; Davis, Gwynne L; Wheeler, Austin C; Stanwood, Gregg D; Hahn, Maureen K; Blakely, Randy D
The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants. Journal Article
In: Proc Natl Acad Sci U S A, vol. 111, no. 44, pp. E4779-88, 2014, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking).
@article{Mergy:2014aa,
title = {The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.},
author = {Marc A Mergy and Raajaram Gowrishankar and Paul J Gresch and Stephanie C Gantz and John Williams and Gwynne L Davis and Austin C Wheeler and Gregg D Stanwood and Maureen K Hahn and Randy D Blakely},
url = {https://www.ncbi.nlm.nih.gov/pubmed/25331903},
doi = {10.1073/pnas.1417294111},
issn = {1091-6490 (Electronic); 0027-8424 (Linking)},
year = {2014},
date = {2014-11-04},
journal = {Proc Natl Acad Sci U S A},
volume = {111},
number = {44},
pages = {E4779-88},
address = {Departments of Pharmacology.},
abstract = {Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.
2013
Gantz, Stephanie C; Ford, Christopher P; Neve, Kim A; Williams, John T
Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway. Journal Article
In: J Neurosci, vol. 31, no. 35, pp. 12629–12637, 2013, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Gantz:2011aa,
title = {Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway.},
author = {Stephanie C Gantz and Christopher P Ford and Kim A Neve and John T Williams},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21880923},
doi = {10.1523/JNEUROSCI.0684-11.2011},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2013},
date = {2013-08-31},
journal = {J Neurosci},
volume = {31},
number = {35},
pages = {12629--12637},
address = {Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.},
abstract = {Mutations in the methyl-CpG-binding protein 2 (MeCP2) result in Rett syndrome (RTT), an X-linked disorder that disrupts neurodevelopment. Girls with RTT exhibit motor deficits similar to those in Parkinson's disease, suggesting defects in the nigrostriatal pathway. This study examined age-dependent changes in dopamine neurons of the substantia nigra (SN) from wild-type, presymptomatic, and symptomatic Mecp2(+/-) mice. Mecp2(+) neurons in the SN in Mecp2(+/-) mice were indistinguishable in morphology, resting conductance, and dopamine current density from neurons in wild-type mice. However, the capacitance, total dendritic length, and resting conductance of Mecp2(-) neurons were less than those of Mecp2(+) neurons as early as 4 weeks after birth, before overt symptoms. These differences were maintained throughout life. In symptomatic Mecp2(+/-) mice, the current induced by activation of D(2) dopamine autoreceptors was significantly less in Mecp2(-) neurons than in Mecp2(+) neurons, although D(2) receptor density was unaltered in Mecp2(+/-) mice. Electrochemical measurements revealed that significantly less dopamine was released after stimulation of striatum in adult Mecp2(+/-) mice compared to wild type. The decrease in size and function of Mecp2(-) neurons observed in adult Mecp2(+/-) mice was recapitulated in dopamine neurons from symptomatic Mecp2(-/y) males. These results show that mutation in Mecp2 results in cell-autonomous defects in the SN early in life and throughout adulthood. Ultimately, dysfunction in terminal dopamine release and D(2) autoreceptor-dependent currents in dopamine neurons from symptomatic females support the idea that decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mutations in the methyl-CpG-binding protein 2 (MeCP2) result in Rett syndrome (RTT), an X-linked disorder that disrupts neurodevelopment. Girls with RTT exhibit motor deficits similar to those in Parkinson's disease, suggesting defects in the nigrostriatal pathway. This study examined age-dependent changes in dopamine neurons of the substantia nigra (SN) from wild-type, presymptomatic, and symptomatic Mecp2(+/-) mice. Mecp2(+) neurons in the SN in Mecp2(+/-) mice were indistinguishable in morphology, resting conductance, and dopamine current density from neurons in wild-type mice. However, the capacitance, total dendritic length, and resting conductance of Mecp2(-) neurons were less than those of Mecp2(+) neurons as early as 4 weeks after birth, before overt symptoms. These differences were maintained throughout life. In symptomatic Mecp2(+/-) mice, the current induced by activation of D(2) dopamine autoreceptors was significantly less in Mecp2(-) neurons than in Mecp2(+) neurons, although D(2) receptor density was unaltered in Mecp2(+/-) mice. Electrochemical measurements revealed that significantly less dopamine was released after stimulation of striatum in adult Mecp2(+/-) mice compared to wild type. The decrease in size and function of Mecp2(-) neurons observed in adult Mecp2(+/-) mice was recapitulated in dopamine neurons from symptomatic Mecp2(-/y) males. These results show that mutation in Mecp2 results in cell-autonomous defects in the SN early in life and throughout adulthood. Ultimately, dysfunction in terminal dopamine release and D(2) autoreceptor-dependent currents in dopamine neurons from symptomatic females support the idea that decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice.
Gantz, Stephanie C; Bunzow, James R; Williams, John T
Spontaneous inhibitory synaptic currents mediated by a G protein-coupled receptor. Journal Article
In: Neuron, vol. 78, no. 5, pp. 807–812, 2013, ISSN: 1097-4199 (Electronic); 0896-6273 (Linking).
@article{Gantz:2013aa,
title = {Spontaneous inhibitory synaptic currents mediated by a G protein-coupled receptor.},
author = {Stephanie C Gantz and James R Bunzow and John T Williams},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23764286},
doi = {10.1016/j.neuron.2013.04.013},
issn = {1097-4199 (Electronic); 0896-6273 (Linking)},
year = {2013},
date = {2013-06-05},
journal = {Neuron},
volume = {78},
number = {5},
pages = {807--812},
address = {Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.},
abstract = {G protein-coupled receptors (GPCRs) affect many physiological processes by modulating both intrinsic membrane conductances and synaptic transmission. This study describes spontaneous miniature inhibitory postsynaptic currents mediated by vesicular dopamine release acting locally on metabotropic D2 receptors leading to the activation of a G protein-coupled inwardly rectifying potassium conductance. Thus, individual exocytotic events result in spontaneous GPCR-mediated transmission, similar to synaptic activation of classical ligand-gated ion channels.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
G protein-coupled receptors (GPCRs) affect many physiological processes by modulating both intrinsic membrane conductances and synaptic transmission. This study describes spontaneous miniature inhibitory postsynaptic currents mediated by vesicular dopamine release acting locally on metabotropic D2 receptors leading to the activation of a G protein-coupled inwardly rectifying potassium conductance. Thus, individual exocytotic events result in spontaneous GPCR-mediated transmission, similar to synaptic activation of classical ligand-gated ion channels.
2010
Ford, Christopher P; Gantz, Stephanie C; Phillips, Paul E M; Williams, John T
Control of extracellular dopamine at dendrite and axon terminals. Journal Article
In: J Neurosci, vol. 30, no. 20, pp. 6975–6983, 2010, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Ford:2010aa,
title = {Control of extracellular dopamine at dendrite and axon terminals.},
author = {Christopher P Ford and Stephanie C Gantz and Paul E M Phillips and John T Williams},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20484639},
doi = {10.1523/JNEUROSCI.1020-10.2010},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2010},
date = {2010-05-19},
journal = {J Neurosci},
volume = {30},
number = {20},
pages = {6975--6983},
address = {Vollum Institute, Oregon Health & Science University L474, Portland, Oregon 97239, USA. fordc@ohsu.edu},
abstract = {Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium dependence of somatodendritic dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was approximately 20-fold greater than in cell body regions of the VTA or SNc. However, the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine transient as measured by fast-scan cyclic voltammetry yet did not alter the kinetics of the dopamine-dependent IPSC. Dextran failed to significantly alter the time course of the rise and fall of the dopamine transient in the striatum, suggesting a more influential role for reuptake in the striatum. The conclusion is that the time course of dopamine within the extracellular space of the VTA is dependent on both diffusion and reuptake, whereas the activation of D(2) receptors on dopamine neurons is primarily limited by reuptake.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium dependence of somatodendritic dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was approximately 20-fold greater than in cell body regions of the VTA or SNc. However, the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine transient as measured by fast-scan cyclic voltammetry yet did not alter the kinetics of the dopamine-dependent IPSC. Dextran failed to significantly alter the time course of the rise and fall of the dopamine transient in the striatum, suggesting a more influential role for reuptake in the striatum. The conclusion is that the time course of dopamine within the extracellular space of the VTA is dependent on both diffusion and reuptake, whereas the activation of D(2) receptors on dopamine neurons is primarily limited by reuptake.
