Contact
Biomedical Research Center251 Bayview Boulevard
Suite 200
Baltimore, MD 21224
Email: marco.pignatelli@nih.gov
Education
Residency (hons)- Sapienza University of Rome
MD (hons) - Sapienza University of Rome
Research Interests
Marco Pignatelli received his MD and Residency in Clinical Pharmacology from Sapienza University of Rome. Next, he joined the Synaptic Plasticity Section of the Cellular Neurobiology research Branch as a Postdoctoral Fellow in the laboratory of Dr. Antonello Bonci. His research focus is driven by two major goals: first, to obtain a mechanistic understanding of how synapses work and contribute to information processing by neural circuits, and ultimately how synapses and neural circuits give rise to complex behaviors; second, to obtain a molecular-based understanding of how synaptopathies might be the subject for therapeutic intervention. Towards this goal, he is using an interdisciplinary approach, drawing upon his training and experience in electrophysiology, molecular pharmacology, cell biology and genetics.
Selected Publications
2018
Pignatelli, Marco; Bonci, Antonello
Spiraling Connectivity of NAc-VTA Circuitry. Journal Article
In: Neuron, vol. 97, no. 2, pp. 261–262, 2018, ISSN: 1097-4199 (Electronic); 0896-6273 (Linking).
@article{Pignatelli:2018aa,
title = {Spiraling Connectivity of NAc-VTA Circuitry.},
author = {Marco Pignatelli and Antonello Bonci},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29346748},
doi = {10.1016/j.neuron.2017.12.046},
issn = {1097-4199 (Electronic); 0896-6273 (Linking)},
year = {2018},
date = {2018-01-17},
journal = {Neuron},
volume = {97},
number = {2},
pages = {261--262},
address = {Synaptic Plasticity Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, Baltimore, MD 21224, USA. Electronic address: marco.pignatelli@nih.gov.},
abstract = {How do nucleus accumbens (NAc) subdivisions shape information flow into distinct ventral tegmental area (VTA) subcircuits? Yang et al. (2018) provide insightful answers to this question by expanding our knowledge about the circuit architecture and function of reciprocal connectivity between NAc and VTA.},
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How do nucleus accumbens (NAc) subdivisions shape information flow into distinct ventral tegmental area (VTA) subcircuits? Yang et al. (2018) provide insightful answers to this question by expanding our knowledge about the circuit architecture and function of reciprocal connectivity between NAc and VTA.
2017
Umanah, George K E; Pignatelli, Marco; Yin, Xiling; Chen, Rong; Crawford, Joshua; Neifert, Stewart; Scarffe, Leslie; Behensky, Adam A; Guiberson, Noah; Chang, Melissa; Ma, Erica; Kim, Jin Wan; Castro, Cibele C; Mao, Xiaobo; Chen, Li; Andrabi, Shaida A; Pletnikov, Mikhail V; Pulver, Ann E; Avramopoulos, Dimitrios; Bonci, Antonello; Valle, David; Dawson, Ted M; Dawson, Valina L
Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel. Journal Article
In: Sci Transl Med, vol. 9, no. 420, 2017, ISSN: 1946-6242 (Electronic); 1946-6234 (Linking).
@article{Umanah:2017aa,
title = {Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel.},
author = {George K E Umanah and Marco Pignatelli and Xiling Yin and Rong Chen and Joshua Crawford and Stewart Neifert and Leslie Scarffe and Adam A Behensky and Noah Guiberson and Melissa Chang and Erica Ma and Jin Wan Kim and Cibele C Castro and Xiaobo Mao and Li Chen and Shaida A Andrabi and Mikhail V Pletnikov and Ann E Pulver and Dimitrios Avramopoulos and Antonello Bonci and David Valle and Ted M Dawson and Valina L Dawson},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29237760},
doi = {10.1126/scitranslmed.aah4985},
issn = {1946-6242 (Electronic); 1946-6234 (Linking)},
year = {2017},
date = {2017-12-17},
journal = {Sci Transl Med},
volume = {9},
number = {420},
address = {Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.},
abstract = {The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.},
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The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission.
Edwards, Nicholas J; Tejeda, Hugo A; Pignatelli, Marco; Zhang, Shiliang; McDevitt, Ross A; Wu, Jocelyn; Bass, Caroline E; Bettler, Bernhard; Morales, Marisela; Bonci, Antonello
Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior. Journal Article
In: Nat Neurosci, vol. 20, no. 3, pp. 438–448, 2017, ISSN: 1546-1726 (Electronic); 1097-6256 (Linking).
@article{Edwards2017,
title = {Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior.},
author = {Nicholas J Edwards and Hugo A Tejeda and Marco Pignatelli and Shiliang Zhang and Ross A McDevitt and Jocelyn Wu and Caroline E Bass and Bernhard Bettler and Marisela Morales and Antonello Bonci},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28114294},
doi = {10.1038/nn.4482},
issn = {1546-1726 (Electronic); 1097-6256 (Linking)},
year = {2017},
date = {2017-03-01},
journal = {Nat Neurosci},
volume = {20},
number = {3},
pages = {438--448},
address = {Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.},
abstract = {Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABAB receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABAB receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.
Pignatelli, Marco; Umanah, George Kwabena Essien; Ribeiro, Sissi Palma; Chen, Rong; Karuppagounder, Senthilkumar Senthil; Yau, Hau-Jie; Eacker, Stephen; Dawson, Valina Lynn; Dawson, Ted Murray; Bonci, Antonello
Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning. Journal Article
In: Neuron, vol. 93, no. 2, pp. 425–440, 2017, ISSN: 1097-4199 (Electronic); 0896-6273 (Linking).
@article{Pignatelli2017,
title = {Synaptic Plasticity onto Dopamine Neurons Shapes Fear Learning.},
author = {Marco Pignatelli and George Kwabena Essien Umanah and Sissi Palma Ribeiro and Rong Chen and Senthilkumar Senthil Karuppagounder and Hau-Jie Yau and Stephen Eacker and Valina Lynn Dawson and Ted Murray Dawson and Antonello Bonci},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28103482},
doi = {10.1016/j.neuron.2016.12.030},
issn = {1097-4199 (Electronic); 0896-6273 (Linking)},
year = {2017},
date = {2017-01-18},
journal = {Neuron},
volume = {93},
number = {2},
pages = {425--440},
address = {Intramural Research Program, Synaptic Plasticity Section, National Institute on Drug Abuse, Baltimore, MD 21224, USA.},
abstract = {Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT+ neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT+ neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT+ neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT+ neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning.
Tejeda, Hugo A; Wu, Jocelyn; Kornspun, Alana R; Pignatelli, Marco; Kashtelyan, Vadim; Krashes, Michael J; Lowell, Brad B; Carlezon, William A Jr; Bonci, Antonello
In: Neuron, vol. 93, no. 1, pp. 147-163, 2017, ISSN: 1097-4199 (Electronic); 0896-6273 (Linking).
@article{Tejeda2017,
title = {Pathway- and Cell-Specific Kappa-Opioid Receptor Modulation of Excitation-Inhibition Balance Differentially Gates D1 and D2 Accumbens Neuron Activity.},
author = {Tejeda, Hugo A and Wu, Jocelyn and Kornspun, Alana R and Pignatelli, Marco and Kashtelyan, Vadim and Krashes, Michael J and Lowell, Brad B and Carlezon, William A Jr and Bonci, Antonello},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28056342},
doi = {10.1016/j.neuron.2016.12.005},
issn = {1097-4199 (Electronic); 0896-6273 (Linking)},
year = {2017},
date = {2017-01-04},
journal = {Neuron},
volume = {93},
number = {1},
pages = {147-163},
abstract = {Endogenous dynorphin signaling via the kappa-opioid receptor (KOR) in the nucleus accumbens (NAcc) powerfully mediates negative affective states and stress reactivity. Excitatory inputs from the hippocampus and amygdala play a fundamental role in shaping the activity of both NAcc D1 and D2 MSNs, which encode positive and negative motivational valences, respectively. However, a circuit-based mechanism by which KOR modulation of excitation-inhibition balance modifies D1 and D2 MSN activity is lacking. Here, we provide a comprehensive synaptic framework wherein presynaptic KOR inhibition decreases the excitatory drive of D1 MSN activity by the amygdala, but not the hippocampus. Conversely, presynaptic inhibition by KORs of inhibitory synapses on D2 MSNs enhances integration of excitatory drive by the amygdala and hippocampus. In conclusion, we describe a circuit-based mechanism showing differential gating of afferent control of D1 and D2 MSN activity by KORs in a pathway-specific manner.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Endogenous dynorphin signaling via the kappa-opioid receptor (KOR) in the nucleus accumbens (NAcc) powerfully mediates negative affective states and stress reactivity. Excitatory inputs from the hippocampus and amygdala play a fundamental role in shaping the activity of both NAcc D1 and D2 MSNs, which encode positive and negative motivational valences, respectively. However, a circuit-based mechanism by which KOR modulation of excitation-inhibition balance modifies D1 and D2 MSN activity is lacking. Here, we provide a comprehensive synaptic framework wherein presynaptic KOR inhibition decreases the excitatory drive of D1 MSN activity by the amygdala, but not the hippocampus. Conversely, presynaptic inhibition by KORs of inhibitory synapses on D2 MSNs enhances integration of excitatory drive by the amygdala and hippocampus. In conclusion, we describe a circuit-based mechanism showing differential gating of afferent control of D1 and D2 MSN activity by KORs in a pathway-specific manner.
2015
Pignatelli, Marco; Bonci, Antonello
Role of Dopamine Neurons in Reward and Aversion: A Synaptic Plasticity Perspective. Journal Article
In: Neuron, vol. 86, no. 5, pp. 1145–1157, 2015, ISSN: 1097-4199 (Electronic); 0896-6273 (Linking).
@article{Pignatelli:2015aa,
title = {Role of Dopamine Neurons in Reward and Aversion: A Synaptic Plasticity Perspective.},
author = {Marco Pignatelli and Antonello Bonci},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26050034},
doi = {10.1016/j.neuron.2015.04.015},
issn = {1097-4199 (Electronic); 0896-6273 (Linking)},
year = {2015},
date = {2015-06-03},
journal = {Neuron},
volume = {86},
number = {5},
pages = {1145--1157},
address = {Intramural Research Program, Synaptic Plasticity Section, National Institute on Drug Abuse, Baltimore, MD 21224, USA.},
abstract = {The brain is wired to predict future outcomes. Experience-dependent plasticity at excitatory synapses within dopamine neurons of the ventral tegmental area, a key region for a broad range of motivated behaviors, is thought to be a fundamental cellular mechanism that enables adaptation to a dynamic environment. Thus, depending on the circumstances, dopamine neurons are capable of processing both positive and negative reinforcement learning strategies. In this review, we will discuss how changes in synaptic plasticity of dopamine neurons may affect dopamine release, as well as behavioral adaptations to different environmental conditions falling at opposite ends of a saliency spectrum ranging from reward to aversion.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The brain is wired to predict future outcomes. Experience-dependent plasticity at excitatory synapses within dopamine neurons of the ventral tegmental area, a key region for a broad range of motivated behaviors, is thought to be a fundamental cellular mechanism that enables adaptation to a dynamic environment. Thus, depending on the circumstances, dopamine neurons are capable of processing both positive and negative reinforcement learning strategies. In this review, we will discuss how changes in synaptic plasticity of dopamine neurons may affect dopamine release, as well as behavioral adaptations to different environmental conditions falling at opposite ends of a saliency spectrum ranging from reward to aversion.
2014
Bonito-Oliva, Alessandra; Pignatelli, Marco; Spigolon, Giada; Yoshitake, Takashi; Seiler, Stefanie; Longo, Francesco; Piccinin, Sonia; Kehr, Jan; Mercuri, Nicola B; Nistico, Robert; Fisone, Gilberto
Cognitive impairment and dentate gyrus synaptic dysfunction in experimental parkinsonism. Journal Article
In: Biol Psychiatry, vol. 75, no. 9, pp. 701–710, 2014, ISSN: 1873-2402 (Electronic); 0006-3223 (Linking).
@article{Bonito-Oliva:2014aa,
title = {Cognitive impairment and dentate gyrus synaptic dysfunction in experimental parkinsonism.},
author = {Alessandra Bonito-Oliva and Marco Pignatelli and Giada Spigolon and Takashi Yoshitake and Stefanie Seiler and Francesco Longo and Sonia Piccinin and Jan Kehr and Nicola B Mercuri and Robert Nistico and Gilberto Fisone},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23541633},
doi = {10.1016/j.biopsych.2013.02.015},
issn = {1873-2402 (Electronic); 0006-3223 (Linking)},
year = {2014},
date = {2014-05-01},
journal = {Biol Psychiatry},
volume = {75},
number = {9},
pages = {701--710},
address = {Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.},
abstract = {BACKGROUND: Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway and the emergence of rigidity, tremor, and bradykinesia. Accumulating evidence indicates that PD is also accompanied by nonmotor symptoms including cognitive deficits, often manifested as impaired visuospatial memory. METHODS: We studied cognitive performance and synaptic plasticity in a mouse model of PD, characterized by partial lesion of the dopaminergic and noradrenergic inputs to striatum and hippocampus. Sham- and 6-hydroxydopamine-lesioned mice were subjected to the novel object recognition test, and long-term potentiation was examined in the dentate gyrus and CA1 regions of the hippocampus. RESULTS: Bilateral 6-hydroxydopamine lesion reduced long-term but not short-term novel object recognition and decreased long-term potentiation specifically in the dentate gyrus. These abnormalities did not depend on the loss of noradrenaline but were abolished by the antiparkinsonian drug, L-DOPA, or by SKF81297, a dopamine D1-type receptor agonist. In contrast, activation of dopamine D2-type receptors did not modify the effects produced by the lesion. Blockade of the extracellular signal-regulated kinases prevented the ability of SKF81297 to rescue novel object recognition and long-term potentiation. CONCLUSIONS: These findings show that partial dopamine depletion leads to impairment of long-term recognition memory accompanied by abnormal synaptic plasticity in the dentate gyrus. They also demonstrate that activation of dopamine D1 receptors corrects these deficits, through a mechanism that requires intact extracellular signal-regulated kinases signaling.},
keywords = {},
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BACKGROUND: Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway and the emergence of rigidity, tremor, and bradykinesia. Accumulating evidence indicates that PD is also accompanied by nonmotor symptoms including cognitive deficits, often manifested as impaired visuospatial memory. METHODS: We studied cognitive performance and synaptic plasticity in a mouse model of PD, characterized by partial lesion of the dopaminergic and noradrenergic inputs to striatum and hippocampus. Sham- and 6-hydroxydopamine-lesioned mice were subjected to the novel object recognition test, and long-term potentiation was examined in the dentate gyrus and CA1 regions of the hippocampus. RESULTS: Bilateral 6-hydroxydopamine lesion reduced long-term but not short-term novel object recognition and decreased long-term potentiation specifically in the dentate gyrus. These abnormalities did not depend on the loss of noradrenaline but were abolished by the antiparkinsonian drug, L-DOPA, or by SKF81297, a dopamine D1-type receptor agonist. In contrast, activation of dopamine D2-type receptors did not modify the effects produced by the lesion. Blockade of the extracellular signal-regulated kinases prevented the ability of SKF81297 to rescue novel object recognition and long-term potentiation. CONCLUSIONS: These findings show that partial dopamine depletion leads to impairment of long-term recognition memory accompanied by abnormal synaptic plasticity in the dentate gyrus. They also demonstrate that activation of dopamine D1 receptors corrects these deficits, through a mechanism that requires intact extracellular signal-regulated kinases signaling.
Pignatelli, Marco; Piccinin, Sonia; Molinaro, Gemma; Menna, Luisa Di; Riozzi, Barbara; Cannella, Milena; Motolese, Marta; Vetere, Gisella; Catania, Maria Vincenza; Battaglia, Giuseppe; Nicoletti, Ferdinando; Nistico, Robert; Bruno, Valeria
In: J Neurosci, vol. 34, no. 13, pp. 4558–4566, 2014, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Pignatelli:2014aa,
title = {Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome.},
author = {Marco Pignatelli and Sonia Piccinin and Gemma Molinaro and Luisa Di Menna and Barbara Riozzi and Milena Cannella and Marta Motolese and Gisella Vetere and Maria Vincenza Catania and Giuseppe Battaglia and Ferdinando Nicoletti and Robert Nistico and Valeria Bruno},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24672001},
doi = {10.1523/JNEUROSCI.1846-13.2014},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2014},
date = {2014-03-26},
journal = {J Neurosci},
volume = {34},
number = {13},
pages = {4558--4566},
abstract = {Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.},
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Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3A(m-/p+) mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.
2013
Pignatelli, Marco; Vollmayr, Barbara; Richter, Sophie Helene; Middei, Silvia; Matrisciano, Francesco; Molinaro, Gemma; Nasca, Carla; Battaglia, Giuseppe; Ammassari-Teule, Martine; Feligioni, Marco; Nistico, Robert; Nicoletti, Ferdinando; Gass, Peter
Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats. Journal Article
In: Neuropharmacology, vol. 66, pp. 339–347, 2013, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking).
@article{Pignatelli:2013aa,
title = {Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats.},
author = {Marco Pignatelli and Barbara Vollmayr and Sophie Helene Richter and Silvia Middei and Francesco Matrisciano and Gemma Molinaro and Carla Nasca and Giuseppe Battaglia and Martine Ammassari-Teule and Marco Feligioni and Robert Nistico and Ferdinando Nicoletti and Peter Gass},
url = {https://www.ncbi.nlm.nih.gov/pubmed/22709946},
doi = {10.1016/j.neuropharm.2012.05.046},
issn = {1873-7064 (Electronic); 0028-3908 (Linking)},
year = {2013},
date = {2013-03-01},
journal = {Neuropharmacology},
volume = {66},
pages = {339--347},
address = {Department of Physiology and Pharmacology, University of Rome },
abstract = {Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression. In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment-resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally. not learned helpless rats (cNLH). Western blot analysis showed an increased expression of mGlu5 (but not mGlu1a) receptors in the hippocampus of cLH rats, as compared with control cNLH rats. We also examined mGlu1/5 receptor signaling by in vivo measurement of DHPG-stimulated polyphosphoinositides hydrolysis. Stimulation of (3)H-inositolmonophosphate formation induced by i.c.v. injection of DHPG was enhanced by about 50% in the hippocampus of cLH rats. Correspondingly, DHPG-induced long-term depression (LTD) at Schaffer collateral/CA1 pyramidal cell synapses was amplified in hippocampal slices of cLH rats, whereas LTD induced by low frequency stimulation of the Schaffer collaterals did not change. Moreover, these effects were associated with decreased basal dendritic spine density of CA1 pyramidal cell in cLH rats. These data raise the attractive possibility that changes in the expression and function of mGlu5 receptors in the hippocampus might underlie the changes in synaptic plasticity associated with the depressive-like phenotype of cLH rats. However, chronic treatment of cLH rats with MPEP did not reverse learned helplessness, indicating that the enhanced mGlu5 receptor function is not the only player in the behavioral phenotype of this genetic model of depression. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression. In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment-resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally. not learned helpless rats (cNLH). Western blot analysis showed an increased expression of mGlu5 (but not mGlu1a) receptors in the hippocampus of cLH rats, as compared with control cNLH rats. We also examined mGlu1/5 receptor signaling by in vivo measurement of DHPG-stimulated polyphosphoinositides hydrolysis. Stimulation of (3)H-inositolmonophosphate formation induced by i.c.v. injection of DHPG was enhanced by about 50% in the hippocampus of cLH rats. Correspondingly, DHPG-induced long-term depression (LTD) at Schaffer collateral/CA1 pyramidal cell synapses was amplified in hippocampal slices of cLH rats, whereas LTD induced by low frequency stimulation of the Schaffer collaterals did not change. Moreover, these effects were associated with decreased basal dendritic spine density of CA1 pyramidal cell in cLH rats. These data raise the attractive possibility that changes in the expression and function of mGlu5 receptors in the hippocampus might underlie the changes in synaptic plasticity associated with the depressive-like phenotype of cLH rats. However, chronic treatment of cLH rats with MPEP did not reverse learned helplessness, indicating that the enhanced mGlu5 receptor function is not the only player in the behavioral phenotype of this genetic model of depression. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
