Paul Greengard

The Rockefeller University, New York, New York, United States

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Publications (858)7528.43 Total impact

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    ABSTRACT: An increase in amyloid-β (Aβ) production is a major pathogenic mechanism associated with Alzheimer's disease (AD), but little is known about possible homeostatic control of the amyloidogenic pathway. Here we report that the amyloid precursor protein (APP) intracellular domain (AICD) downregulates Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1 (WAVE1 or WASF1) as part of a negative feedback mechanism to limit Aβ production. The AICD binds to the Wasf1 promoter, negatively regulates its transcription and downregulates Wasf1 mRNA and protein expression in Neuro 2a (N2a) cells. WAVE1 interacts and colocalizes with APP in the Golgi apparatus. Experimentally reducing WAVE1 in N2a cells decreased the budding of APP-containing vesicles and reduced cell-surface APP, thereby reducing the production of Aβ. WAVE1 downregulation was observed in mouse models of AD. Reduction of Wasf1 gene expression dramatically reduced Aβ levels and restored memory deficits in a mouse model of AD. A decrease in amounts of WASF1 mRNA was also observed in human AD brains, suggesting clinical relevance of the negative feedback circuit involved in homeostatic regulation of Aβ production.
    Nature medicine 08/2015; DOI:10.1038/nm.3924 · 28.05 Impact Factor
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    ABSTRACT: For degenerative disorders of the CNS, the main obstacle to therapeutic advancement has been the challenge of identifying the key molecular mechanisms underlying neuronal loss. We developed a combinatorial approach including translational profiling and brain regulatory network analysis to search for key determinants of neuronal survival or death. Following the generation of transgenic mice for cell type-specific profiling of midbrain dopaminergic neurons, we established and compared translatome libraries reflecting the molecular signature of these cells at baseline or under degenerative stress. Analysis of these libraries by interrogating a context-specific brain regulatory network led to the identification of a repertoire of intrinsic upstream regulators that drive the dopaminergic stress response. The altered activity of these regulators was not associated with changes in their expression levels. This strategy can be generalized for the identification of molecular determinants involved in the degeneration of other classes of neurons.
    Nature Neuroscience 07/2015; DOI:10.1038/nn.4070 · 14.98 Impact Factor
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    ABSTRACT: The cAMP and cAMP-dependent protein kinase A (PKA) signaling cascade is a ubiquitous pathway acting downstream of multiple neuromodulators. We found that the phosphorylation of phosphodiesterase-4 (PDE4) by cyclin-dependent protein kinase 5 (Cdk5) facilitated cAMP degradation and homeostasis of cAMP/PKA signaling. In mice, loss of Cdk5 throughout the forebrain elevated cAMP levels and increased PKA activity in striatal neurons, and altered behavioral responses to acute or chronic stressors. Ventral striatum- or D1 dopamine receptor-specific conditional knockout of Cdk5, or ventral striatum infusion of a small interfering peptide that selectively targeted the regulation of PDE4 by Cdk5, produced analogous effects on stress-induced behavioral responses. Together, our results demonstrate that altering cAMP signaling in medium spiny neurons of the ventral striatum can effectively modulate stress-induced behavioral states. We propose that targeting the Cdk5 regulation of PDE4 could be a new therapeutic approach for clinical conditions associated with stress, such as depression.
    Nature Neuroscience 07/2015; DOI:10.1038/nn.4066 · 14.98 Impact Factor
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    ABSTRACT: Δ9-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudate-putamen and nucleus accumbens. However, the molecular events that underlie these interactions following THC treatment are not well understood. The current study showed that pretreatment with dopamine D1 receptor (D1R) antagonists prior to repeated administration of THC attenuated induction of ΔFosB in the nucleus accumbens, caudate-putamen, amygdala and prefrontal cortex. Anatomical studies showed that repeated THC induced ΔFosB in D1R containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation-specific effects of dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP 32), which regulates protein kinase A signaling. Genetic deletion of DARPP-32 attenuated ΔFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THC was then acutely or repeatedly administered to wild-type and DARPP 32 KO mice, and in vivo responses were measured. DARPP 32 KO mice exhibited enhanced acute THC-mediated hypolocomotion and developed greater tolerance to this response relative to wild-type mice. Agonist-stimulated [35S]GTPγS binding showed that cannabinoid-stimulated G-protein activity did not differ between DARPP 32 KO and wild-type mice treated with vehicle or repeated THC. These results indicate that D1Rs play a major role in THC-mediated ΔFosB induction in the forebrain, whereas the role of DARPP 32 in THC-mediated ΔFosB induction and modulation of motor activity appears to be more complex. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 06/2015; DOI:10.1124/jpet.115.224428 · 3.86 Impact Factor
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    ABSTRACT: Metabotropic glutamate receptor 5 (mGluR5) regulates excitatory postsynaptic signaling in the central nervous system (CNS) and is implicated in various CNS disorders. Protein kinase A (PKA) signaling is known to play a critical role in neuropsychiatric disorders such as Parkinson's disease, schizophrenia and addiction. Dopamine signaling is known to modulate the properties of mGluR5 in a cAMP- and PKA-dependent manner, suggesting that mGluR5 may be a direct target for PKA. Our study identifies mGluR5 at Ser870 as a direct substrate for PKA phosphorylation and demonstrates that this phosphorylation plays a critical role in the PKA-mediated modulation of mGluR5 functions such as extracellular signal-regulated kinase (ERK) phosphorylation and intracellular Ca(2+) oscillations. The identification of the molecular mechanism by which PKA signaling modulates mGluR5-mediated cellular responses contributes to the understanding of the interaction between dopaminergic and glutamatergic neuronal signaling. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 02/2015; 132(6). DOI:10.1111/jnc.13038 · 4.24 Impact Factor
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    Lars Brichta · Paul Greengard
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    ABSTRACT: Numerous disorders of the central nervous system (CNS) are attributed to the selective death of distinct neuronal cell populations. Interestingly, in many of these conditions, a specific subset of neurons is extremely prone to degeneration while other, very similar neurons are less affected or even spared for many years. In Parkinson's disease (PD), the motor manifestations are primarily linked to the selective, progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). In contrast, the very similar DA neurons in the ventral tegmental area (VTA) demonstrate a much lower degree of degeneration. Elucidating the molecular mechanisms underlying the phenomenon of differential DA vulnerability in PD has proven extremely challenging. Moreover, an increasing number of studies demonstrate that considerable molecular and electrophysiologic heterogeneity exists among the DA neurons within the SNpc as well as those within the VTA, adding yet another layer of complexity to the selective DA vulnerability observed in PD. The discovery of key pathways that regulate this differential susceptibility of DA neurons to degeneration holds great potential for the discovery of novel drug targets and the development of promising neuroprotective treatment strategies. This review provides an update on the molecular basis of the differential vulnerability of midbrain DA neurons in PD and highlights the most recent developments in this field.
    Frontiers in Neuroanatomy 12/2014; 8:152. DOI:10.3389/fnana.2014.00152 · 4.18 Impact Factor
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    ABSTRACT: Recurrent axon collaterals are a major means of communication between spiny projection neurons (SPNs) in the striatum and profoundly affect the function of the basal ganglia. However, little is known about the molecular and cellular mechanisms that underlie this communication. We show that intrastriatal nitric oxide (NO) signaling elevates the expression of the vesicular GABA transporter (VGAT) within recurrent collaterals of SPNs. Down-regulation of striatal NO signaling resulted in an attenuation of GABAergic signaling in SPN local collaterals, down-regulation of VGAT expression in local processes of SPNs, and impaired motor behavior. PKG1 and cAMP response element-binding protein are involved in the signal transduction that transcriptionally regulates VGAT by NO. These data suggest that transcriptional control of the vesicular GABA transporter by NO regulates GABA transmission and action selection.
    Proceedings of the National Academy of Sciences 11/2014; 111(49). DOI:10.1073/pnas.1420162111 · 9.81 Impact Factor
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    ABSTRACT: Background The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the Nucleus Accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10) specifically in the NAc elicits depressive-like behaviors in mice but its role in drug addiction is unknown. Methods We combine mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (6 to 8 mice per group) and molecular correlates (3 experiments, 5 to 8 mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (5 to 8 mice per group) Results We demonstrate that p11 knockout mice have enhanced cocaine conditioned place preference (CPP), which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine CPP. Finally, we identify dopamine receptor-1 (D1) expressing medium spiny neurons (MSNs) as key mediators of p11’s effects on cocaine reward. Conclusions Our data provide evidence that disruption of p11 homeostasis in the NAc particularly in D1-expressing MSNs may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction.
    Biological psychiatry 11/2014; 76(10). DOI:10.1016/j.biopsych.2014.02.012 · 9.47 Impact Factor
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    ABSTRACT: The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses
    Nature Communications 10/2014; 5(5316). DOI:10.1038/ncomms6316. · 10.74 Impact Factor
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    ABSTRACT: STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.
    PLoS Biology 08/2014; 12(8):e1001923. DOI:10.1371/journal.pbio.1001923 · 11.77 Impact Factor
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    ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The debilitating choreic movements that plague HD patients have been attributed to striatal degeneration induced by the loss of cortically supplied brain-derived neurotrophic factor (BDNF). Here, we show that in mouse models of early symptomatic HD, BDNF delivery to the striatum and its activation of tyrosine-related kinase B (TrkB) receptors were normal. However, in striatal neurons responsible for movement suppression, TrkB receptors failed to properly engage postsynaptic signaling mechanisms controlling the induction of potentiation at corticostriatal synapses. Plasticity was rescued by inhibiting p75 neurotrophin receptor (p75NTR) signaling or its downstream target phosphatase-and-tensin-homolog-deleted-on-chromosome-10 (PTEN). Thus, corticostriatal synaptic dysfunction early in HD is attributable to a correctable defect in the response to BDNF, not its delivery.
    Neuron 07/2014; 83(1):178-188. DOI:10.1016/j.neuron.2014.05.032 · 15.98 Impact Factor
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    ABSTRACT: Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2014; 34(24):8259-67. DOI:10.1523/JNEUROSCI.4368-13.2014 · 6.75 Impact Factor
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    ABSTRACT: Cellular diversity and architectural complexity create barriers to understanding the function of the mammalian CNS at a molecular level. To address this problem, we have recently developed a methodology that provides the ability to profile the entire translated mRNA complement of any genetically defined cell population. This methodology, which we termed translating ribosome affinity purification, or TRAP, combines cell type-specific transgene expression with affinity purification of translating ribosomes. TRAP can be used to study the cell type-specific mRNA profiles of any genetically defined cell type, and it has been used in organisms ranging from Drosophila melanogaster to mice and human cultured cells. Unlike other methodologies that rely on microdissection, cell panning or cell sorting, the TRAP methodology bypasses the need for tissue fixation or single-cell suspensions (and the potential artifacts that these treatments introduce) and reports on mRNAs in the entire cell body. This protocol provides a step-by-step guide to implement the TRAP methodology, which takes 2 d to complete once all materials are in hand.
    Nature Protocol 06/2014; 9(6):1282-91. DOI:10.1038/nprot.2014.085 · 8.36 Impact Factor
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    ABSTRACT: The prediction of treatment response in many neuropsychiatric disorders would be facilitated by easily accessible biomarkers. Using flow cytometry, we herein demonstrate correlations between early reductions of p11 levels in Natural Killer (NK) cells and monocytes and antidepressant response to citalopram in patients with major depressive disorder (MDD).
    Molecular Psychiatry 03/2014; 19(9). DOI:10.1038/mp.2014.13 · 15.15 Impact Factor
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    ABSTRACT: Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic adaptations involving several signaling modulators, activator protein-1-dependent gene expression remains highly dysregulated in direct pathway SPNs upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.
    Proceedings of the National Academy of Sciences 03/2014; 111(12). DOI:10.1073/pnas.1401819111 · 9.81 Impact Factor
  • Yuan Tian · Jerry C Chang · Paul Greengard · Marc Flajolet
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    ABSTRACT: We have reported previously that autophagy is responsible for amyloid precursor potein-C-terminal fragment (APP-CTF) degradation and therefore Aβ clearance. To elucidate the underlying mechanism, using LC3 affinity purification and mass spectrometry analysis, immunoprecipitation (IP), as well as live imaging analysis, we identified and demonstrated that the adaptor-related protein complex 2 (AP2) and PICALM (phosphatidylinositol binding clathrin assembly protein) are in a complex with LC3 and APP-CTF. Taken together, this new set of data suggests that the AP2-PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-dependent autophagic degradation pathway. Interestingly this AP2-LC3 connection seems to be involved in chemically-induced APP-CTF clearance as we observed using the small compound SMER28. The effect observed following SMER28 was significantly reduced after silencing AP2. While more work is required to elucidate the detailed molecular mechanisms involved, our actual data suggest that there is some level of specificity in the steps mentioned above.
    Autophagy 01/2014; 10(4). DOI:10.4161/auto.27802 · 11.42 Impact Factor
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    ABSTRACT: The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks and excitability. miR-128 governs motor activity by suppressing the expression of various ion channels and signaling components of the extracellular signal–regulated kinase ERK2 network that regulate neuronal excitability. In mice, a reduction of miR-128 expression in postnatal neurons causes increased motor activity and fatal epilepsy. Overexpression of miR-128 attenuates neuronal responsiveness, suppresses motor activity, and alleviates motor abnormalities associated with Parkinson’s–like disease and seizures in mice. These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy and movement disorders.
    Science 12/2013; 342(6163):1254-8. DOI:10.1126/science.1244193 · 31.48 Impact Factor
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    Yuan Tian · Jerry C Chang · Emily Y Fan · Marc Flajolet · Paul Greengard
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    ABSTRACT: The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-β (Aβ) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP-CTF) degradation and amyloid β clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid β. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD.
    Proceedings of the National Academy of Sciences 09/2013; 110(42). DOI:10.1073/pnas.1315110110 · 9.81 Impact Factor

Publication Stats

71k Citations
7,528.43 Total Impact Points


  • 1983–2015
    • The Rockefeller University
      • Laboratory of Molecular and Cellular Neuroscience
      New York, New York, United States
    • California Institute of Technology
      Pasadena, California, United States
    • Columbia University
      • College of Physicians and Surgeons
      New York, New York, United States
  • 2010
    • Weill Cornell Medical College
      New York, New York, United States
  • 2006
    • Intra-Cellular Therapies, Inc.
      New York City, New York, United States
    • University of Texas at Dallas
      Richardson, Texas, United States
    • Vanderbilt University
      Nashville, Michigan, United States
  • 1983–2006
    • Cornell University
      • • Department of Neurology and Neuroscience
      • • Department of Ophthalmology
      • • School of Applied and Engineering Physics
      Итак, New York, United States
  • 2005
    • Kurume University
      Куруме, Fukuoka, Japan
  • 2004
    • Ludwig-Maximilian-University of Munich
      • Anatomical Institute
      München, Bavaria, Germany
  • 2003–2004
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 1988–2002
    • Karolinska Institutet
      • Department of Neuroscience
      Сольна, Stockholm, Sweden
  • 1997–2000
    • University of Rome Tor Vergata
      • Dipartimento di Dirito Pubblico
      Roma, Latium, Italy
  • 1985–1999
    • CUNY Graduate Center
      New York, New York, United States
  • 1998
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1995
    • San Raffaele Scientific Institute
      Milano, Lombardy, Italy
    • Florida State University
      • Program in Neuroscience
      Tallahassee, Florida, United States
    • University of Oslo
      Kristiania (historical), Oslo, Norway
  • 1993
    • Boston University
      • Department of Health Sciences
      Boston, Massachusetts, United States
  • 1991
    • Danderyds Sjukhus AB
      Tukholma, Stockholm, Sweden
  • 1990
    • National Research Council
      Roma, Latium, Italy
  • 1984–1990
    • University of Milan
      • Center of Cytopharmacology CNR
      Milano, Lombardy, Italy
    • Kansas State University
      • Department of Biology
      Манхэттен, Kansas, United States
  • 1974–1989
    • Yale University
      • • Department of Molecular Biophysics and Biochemistry
      • • Department of Pharmacology
      • • Department of Psychiatry
      New Haven, CT, United States
  • 1975–1987
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1986
    • Ecole Normale Supérieure de Paris
      • Laboratoire de Géologie
      Lutetia Parisorum, Île-de-France, France