Peter H. Seeburg

Max Planck Institute for Medical Research, Heidelburg, Baden-Württemberg, Germany

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Publications (585)5028.31 Total impact

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    [Show abstract] [Hide abstract] ABSTRACT: Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.
    Full-text · Article · Mar 2016 · Neuron
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    [Show abstract] [Hide abstract] ABSTRACT: N-methyl-D-aspartate receptors (NMDARs) in all hippocampal areas play an essential role in distinct processes of memory formation as well as in sustaining cell survival of postnatally generated neurons in the dentate gyrus (DG). In contrast to the beneficial effects, over-activation of NMDARs has been implicated in many acute and chronic neurological diseases, reason why therapeutic approaches and clinical trials involving receptor blockade have been envisaged for decades. Here we employed genetically engineered mice to study the long-term effect of NMDAR ablation on selective hippocampal neuronal populations. Ablation of either GluN1 or GluN2B causes degeneration of the DG. The neuronal demise affects mature neurons specifically in the dorsal DG and is NMDAR subunit-dependent. Most importantly, the degenerative process exacerbates with increasing age of the animals. These results lead us to conclude that mature granule cells in the dorsal DG undergo neurodegeneration following NMDAR ablation in aged mouse. Thus, caution needs to be exerted when considering long-term administration of NMDAR antagonists for therapeutic purposes.
    Full-text · Article · Dec 2015 · Frontiers in Molecular Neuroscience
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    [Show abstract] [Hide abstract] ABSTRACT: Adenosine-to-inosine (A-to-I) editing is a highly prevalent post-transcriptional modification of RNA, mediated by ADAR enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1 we generated mice with an editing deficient knock-in mutation (Adar1(E861A)). Adar1(E861A/E861A) embryos died at ~E13.5, with activated interferon and dsRNA sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyper-editing within long dsRNA stem loops within 3'UTRs of endogenous transcripts. Finally, embryonic death and phenotypes of the Adar1(E861A/E861A) were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts. Copyright © 2015, American Association for the Advancement of Science.
    Full-text · Article · Jul 2015 · Science
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    Full-text · Conference Paper · Aug 2014
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    [Show abstract] [Hide abstract] ABSTRACT: The hippocampus and the parahippocampal region have been proposed to contribute to path integration. Mice lacking GluA1-containing AMPA receptors (GluA1(-/-) mice) were previously shown to exhibit impaired hippocampal place cell selectivity. Here we investigated whether path integration performance and the activity of grid cells of the medial entorhinal cortex (MEC) are affected in these mice. We first tested GluA1(-/-) mice on a standard food-carrying homing task and found that they were impaired in processing idiothetic cues. To corroborate these findings, we developed an L-maze task that is less complex and is performed entirely in darkness, thereby reducing numerous confounding variables when testing path integration. Also in this task, the performance of GluA1(-/-) mice was impaired. Next, we performed in vivo recordings in the MEC of GluA1(-/-) mice. MEC neurons exhibited altered grid cell spatial periodicity and reduced spatial selectivity, whereas head direction tuning and speed modulation were not affected. The firing associations between pairs of neurons in GluA1(-/-) mice were stable, both in time and space, indicating that attractor states were still present despite the lack of grid periodicity. Together, these results support the hypothesis that spatial representations in the hippocampal-entorhinal network contribute to path integration.
    Preview · Article · Apr 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
  • [Show abstract] [Hide abstract] ABSTRACT: Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both memory and anxiety.
    No preview · Article · Feb 2014 · Nature Reviews Neuroscience
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    [Show abstract] [Hide abstract] ABSTRACT: The idea that an NMDA receptor (NMDAR)-dependent long-term potentiation-like process in the hippocampus is the neural substrate for associative spatial learning and memory has proved to be extremely popular and influential. However, we recently reported that mice lacking NMDARs in dentate gyrus and CA1 hippocampal subfields (GluN1(ΔDGCA1) mice) acquired the open field, spatial reference memory watermaze task as well as controls, a result that directly challenges this view. Here, we show that GluN1(ΔDGCA1) mice were not impaired during acquisition of a spatial discrimination watermaze task, during which mice had to choose between two visually identical beacons, based on extramaze spatial cues, when all trials started at locations equidistant between the two beacons. They were subsequently impaired on test trials starting from close to the decoy beacon, conducted post-acquisition. GluN1(ΔDGCA1) mice were also impaired during reversal of this spatial discrimination. Thus, contrary to the widely held belief, hippocampal NMDARs are not required for encoding associative, long-term spatial memories. Instead, hippocampal NMDARs, particularly in CA1, act as part of a comparator system to detect and resolve conflicts arising when two competing, behavioural response options are evoked concurrently, through activation of a behavioural inhibition system. These results have important implications for current theories of hippocampal function.
    Full-text · Article · Jan 2014 · Philosophical Transactions of The Royal Society B Biological Sciences
  • [Show abstract] [Hide abstract] ABSTRACT: Spatial working memory (SWM), the ability to process and manipulate spatial information over a relatively short period of time, requires an intact hippocampus, but also involves other forebrain nuclei in both in rodents and humans. Previous studies in mice showed that the molecular mechanism of SWM includes activation of AMPA receptors containing the GluA1 subunit (encoded by gria1) as GluA1 deletion in the whole brain (gria1(-/-) ) results in strong SWM deficit However, since these mice globally lack GluA1, the circuit mechanisms of GluA1 contribution to SWM remain unknown. In this study, by targeted expression of GluA1 containing AMPA receptors in the forebrain of gria1(-/-) mice or by removing GluA1 selectively from hippocampus of mice with 'floxed' GluA1 alleles (gria1(fl/fl) ), we show that SWM requires GluA1 action in cortical circuits but is only partially dependent on GluA1-containing AMPA receptors in hippocampus. We further show that hippocampal GluA1 contribution to SWM is temporally restricted and becomes prominent at longer retention intervals (≥30 s). These findings provide a novel insight into the neural circuits required for SWM processing and argue that AMPA mediated signaling across forebrain and hippocampus differentially contribute to encoding of SWM. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Dec 2013 · Hippocampus
  • Rolf Sprengel · Peter H. Seeburg
    [Show abstract] [Hide abstract] ABSTRACT: On this planet, the mammalian brain is probably the most complex cellular network. In this system, glutamate is the dominant neurotransmitter, and it mediates the fast communication between the units of the network. Glutamate’s main sites of action are the ionotropic glutamate receptors (iGluRs) and G-protein-coupled metabotropic glutamate receptors (mGluRs) (Fig. 3.1). iGluRs are a group of receptors that are related in their amino acid sequences and belong to the huge super family of ion channels containing a P-loop as ion-pore-forming segment. These P-loop channels consist of several subunits. In the case of iGluRs, this subunit assembly is tetrameric. Each iGluR subunit has an extracellular amino-terminal domain, three membrane-spanning helices, and the P-loop between helices M1 and M3. On each subunit, the ligand binds to an extracellular glutamate-binding site formed by the two extracellular domains of the subunit. Glutamate binding leads to a bending of helix M1 and M2, followed by an opening of the channel. The P-loops of the four subunits form the channel pore and determine whether the ion channel is selective for monovalent or divalent ions (or both). The carboxy-terminus lies within the cell and can interact with intracellular signaling and scaffolding proteins. Most iGluRs are associated with auxiliary proteins. The auxiliary proteins can be involved in surface delivery and trafficking of the iGluR, but they can also modulate iGluR channel properties. Some of these auxiliary proteins are obligatory for iGluRs, while others are facultative modifiers. The iGluR family consists of four subgroups: AMPA, NMDA, kainate, and orphan receptors (Fig. 3.1), distinguished by their pharmacological profile. Each subgroup has a particular function. Kainate and orphan receptors have not yet been characterized in detail: The kainate receptors form fast channels, but no ion channel function has so far been found for the orphan receptors. The AMPA receptors are strongly expressed everywhere in the brain. They are directly responsible for the fast signal transmission at synapses, which represent the communication points between the individual units (nerve cells, also termed neurons). A similar strong expression has been found for the NMDA receptors. However, the NMDA receptors do not directly participate in fast synaptic transmission; instead, they are the most fundamental modulators of the strength of the synaptic AMPA receptor currents. Most importantly, the NMDA receptor-induced modulation of the AMPA receptor currents at the junctions between neurons is a basis for network formation during development. Moreover, in the mature brain, the NMDA receptors keep synapses modifiable and thus permit a continuous incorporation or removal of new information into and from the network; in other words, the NMDA receptors are necessary for the formation and the extinction of memory. This simple picture of iGluR functions is, however, likely to be substantially modified in the future, in view of the great complexity of the iGluR system described below.
    No preview · Article · Nov 2013
  • No preview · Article · Oct 2013 · European Neuropsychopharmacology
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    [Show abstract] [Hide abstract] ABSTRACT: Pain alters opioid reinforcement, via neuroadaptations within ascending pain pathways interacting with the limbic system. Nerve injury increases expression of glutamate receptors and Homer scaffolding proteins throughout the pain processing pathway and these molecules regulate behavioral sensitivity to various addictive drugs. Thus, we investigated a role for Homers in the interactions between pain and drug reward in mice. Chronic constriction injury of the sciatic nerve (CCI) elevated Homer1b/c and/or Homer2a/b within all mesolimbic structures examined and the Homer increases coincided with elevated mGluR5, GluN2A/B, and the activational state of down-stream kinases. Behaviorally, CCI mice showed pain hypersensitivity and a conditioned place-aversion (CPA) at a low heroin dose that supported conditioned place-preference (CPP) in naïve controls. Null mutations of Homer1a, Homer1 and Homer2, as well as transgenic disruption of mGluR5-Homer interactions, either attenuated or completely blocked low-dose heroin CPP, and none of the CCI mutant strains exhibited heroin-induced CPA. However, heroin CPP did not depend upon full Homer1c expression within the nucleus accumbens (NAC), as CPP occurred in controls infused locally with shRNA-Homer1c, although intra-NAC and/or intrathecal cDNA-Homer1c, -Homer1a and –Homer2b infusions (to best mimic CCI’s effects) were sufficient to blunt heroin CPP in uninjured mice. However, arguing against a simple role for CCI-induced increases in either spinal or NAC Homer expression for heroin CPA, cDNA infusion of our various cDNA constructs either did not affect (intrathecal) or attenuated (NAC) heroin CPA. These data implicate increases in glutamate receptor/Homer/kinase activity within limbic structures, perhaps outside the NAC, as possibly critical for switching the incentive motivational properties of heroin following nerve injury, which has relevance for opioid psychopharmacology in individuals suffering from neuropathic pain.
    Full-text · Article · Jun 2013 · Frontiers in Psychiatry
  • [Show abstract] [Hide abstract] ABSTRACT: To investigate whether alterations in RNA editing (an enzymatic base-specific change to the RNA sequence during primary transcript formation from DNA) of neurotransmitter receptor genes and of transmembrane ion channel genes play a role in human temporal lobe epilepsy (TLE), this exploratory study analyzed 14 known cerebral editing sites in RNA extracted from the brain tissue of 41 patients who underwent surgery for mesial TLE, 23 with hippocampal sclerosis (MTLE+HS). Because intraoperatively sampled RNA cannot be obtained from healthy controls and the best feasible control is identically sampled RNA from patients with a clinically shorter history of epilepsy, the primary aim of the study was to assess the correlation between epilepsy duration and RNA editing in the homogenous group of MTLE+HS. At the functionally relevant I/V site of the voltage-gated potassium channel Kv1.1, an inverse correlation of RNA editing was found with epilepsy duration (r = -0.52, p = 0.01) but not with patient age at surgery, suggesting a specific association with either the epileptic process itself or its antiepileptic medication history. No significant correlations were found between RNA editing and clinical parameters at other sites within glutamate receptor or serotonin 2C receptor gene transcripts. An "all-or-none" (≥95% or ≤5%) editing pattern at most or all sites was discovered in 2 patients. As a secondary part of the study, RNA editing was also analyzed as in the previous literature where up to now, few single editing sites were compared with differently obtained RNA from inhomogenous patient groups and autopsies, and by measuring editing changes in our mouse model. The present screening study is first to identify an editing site correlating with a clinical parameter, and to also provide an estimate of the possible effect size at other sites, which is a prerequisite for power analysis needed in planning future studies.
    No preview · Article · Apr 2013 · Neurobiology of Disease
  • No preview · Article · Mar 2013 · European Neuropsychopharmacology
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    Full-text · Dataset · Jan 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Glutamate receptor dependent synaptic plasticity plays an important role in the pathophysiology of depression. Hippocampal samples from clinically depressed patients display reduced mRNA levels for GluA1, a major subunit of AMPA receptors. Moreover, activation and synaptic incorporation of GluA1-containing AMPA receptors is required for the antidepressant-like effects of NMDA receptor antagonists. These findings argue that GluA1-dependent synaptic plasticity might be critically involved in expression of depression. Using an animal model of depression, we demonstrate that global or hippocampus-selective deletion of GluA1 impairs expression of experience-dependent behavioral despair. This impairment is mediated by the interaction of GluA1 with PDZ-binding domain proteins, as deletion of the C-terminal leucine alone is sufficient to replicate the behavioral phenotype. Our results provide evidence for a significant role of hippocampal GluA1-containing AMPA receptors and their PDZ-interaction in experience-dependent expression of behavioral despair and link mechanisms of hippocampal synaptic plasticity with behavioral expression of depression.
    No preview · Article · Dec 2012 · Neurobiology of Disease
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    Full-text · Conference Paper · Oct 2012
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    [Show abstract] [Hide abstract] ABSTRACT: Hippocampal NMDA receptors (NMDARs) and NMDAR-dependent synaptic plasticity are widely considered crucial substrates of long-term spatial memory, although their precise role remains uncertain. Here we show that Grin1(ΔDGCA1) mice, lacking GluN1 and hence NMDARs in all dentate gyrus and dorsal CA1 principal cells, acquired the spatial reference memory water maze task as well as controls, despite impairments on the spatial reference memory radial maze task. When we ran a spatial discrimination water maze task using two visually identical beacons, Grin1(ΔDGCA1) mice were impaired at using spatial information to inhibit selecting the decoy beacon, despite knowing the platform's actual spatial location. This failure could suffice to impair radial maze performance despite spatial memory itself being normal. Thus, these hippocampal NMDARs are not essential for encoding or storing long-term, associative spatial memories. Instead, we demonstrate an important function of the hippocampus in using spatial knowledge to select between alternative responses that arise from competing or overlapping memories.
    Full-text · Article · Jul 2012 · Nature Neuroscience
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    V Grinevich · P H Seeburg · M K Schwarz · D Jezova
    [Show abstract] [Hide abstract] ABSTRACT: Homer 1 gene products are involved in the regulation of synaptic transmission and plasticity. Beside other deficits, the Homer 1 knockout (KO) mice show distinct behavioural abnormalities, such as anxiety and depression-like behaviours. In addition, we recently reported that the global deletion of the Homer 1 proteins in mice leads to a conspicuous endocrine phenotype linked to hypertrophy of the adrenal cortex, elevated basal and/or adrenocorticotropic hormone-induced corticosterone and aldosterone release in vitro and in vivo, as well as a drastic increase in the adrenocorticotropic hormone receptor mRNA in the adrenocortical cells. Interestingly, the basal secretion of adrenocorticotropic hormone was not changed in these mutants, which is in line with our recent observations, suggesting that the central limb of the hypothalamic-pituitary-adrenal axis (namely hypothalamic corticotropin-releasing hormone levels and the activation of its neurons in response to restraint stress) is not affected in the Homer 1 KO mice. On the contrary, the elevation of both plasma and intra-adrenal corticosterone and aldosterone concentrations in these mutants clearly indicates that the alteration primarily occurred in the adrenal cortex. We propose that excessive steroid release may contribute to depression- and anxiety-like behaviours and that the Homer 1 gene products may be involved in the pathogenesis of these stress-related mood disorders. Keywords: Homer 1, HPA axis, CRH, ACTH, adrenal cortex, corticosterone, aldosterone.
    Full-text · Article · Jul 2012 · Endocrine regulations
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    Joshua J C Rosenthal · Peter H Seeburg
    [Show abstract] [Hide abstract] ABSTRACT: RNA editing by adenosine deamination is a process used to diversify the proteome. The expression of ADARs, the editing enzymes, is ubiquitous among true metazoans, and so adenosine deamination is thought to be universal. By changing codons at the level of mRNA, protein function can be altered, perhaps in response to physiological demand. Although the number of editing sites identified in recent years has been rising exponentially, their effects on protein function, in general, are less well understood. This review assesses the state of the field and highlights particular cases where the biophysical alterations and functional effects caused by RNA editing have been studied in detail.
    Full-text · Article · May 2012 · Neuron
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    Andrei Rozov · Rolf Sprengel · Peter H Seeburg
    [Show abstract] [Hide abstract] ABSTRACT: The GluA2 subunit in heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels restricts Ca(2+) permeability and block by polyamines, rendering linear the current-voltage relationship of these glutamate-gated cation channels. Although GluA2-lacking synaptic AMPA receptors occur in GABA-ergic inhibitory neurons, hippocampal CA1 pyramidal cell synapses are widely held to feature only GluA2 containing AMPA receptors. A controversy has arisen from reports of GluA2-lacking AMPA receptors at hippocampal CA3-to-CA1 cell synapses and a study contesting these findings. Here we sought independent evidence for the presence of GluA2-lacking AMPA receptors in CA1 pyramidal cell synapses by probing the sensitivity of their gated cation channels in wild-type (WT) mice and gene-targeted mouse mutants to philanthotoxin, a specific blocker of GluA2-lacking AMPA receptors. The mutants either lacked GluA2 for maximal philanthotoxin sensitivity, or, for minimal sensitivity, expressed GluA1 solely in a Q/R site-edited version or not at all. Our comparative electrophysiological analyses provide incontrovertible evidence for the presence in wild-type CA1 pyramidal cell synapses of GluA2-less AMPA receptor channels. This article is part of a Special Issue entitled "Calcium permeable AMPARs in synaptic plasticity and disease."
    Full-text · Article · Feb 2012 · Frontiers in Molecular Neuroscience

Publication Stats

82k Citations
5,028.31 Total Impact Points


  • 1991-2015
    • Max Planck Institute for Medical Research
      • Department of Molecular Neurobiology
      Heidelburg, Baden-Württemberg, Germany
    • European Molecular Biology Laboratory
      Heidelburg, Baden-Württemberg, Germany
  • 1987-2012
    • Universität Heidelberg
      • • Center for Molecular Biology (ZMBH)
      • • Department of Molecular Biology
      Heidelburg, Baden-Württemberg, Germany
    • University of Vienna
      • Institut für Biologische Chemie
      Wien, Vienna, Austria
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2008
    • Cardiff University
      • School of Psychology
      Cardiff, Wales, United Kingdom
  • 1998-2006
    • University of Oslo
      Kristiania (historical), Oslo, Norway
    • Max Planck Institute of Molecular Physiology
      Dortmund, North Rhine-Westphalia, Germany
  • 2005
    • University of Oxford
      • Department of Experimental Psychology
      Oxford, England, United Kingdom
  • 2004
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 1982-2004
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2001
    • University of Turku
      Turku, Varsinais-Suomi, Finland
  • 1999
    • Zentrum für Molekulare Neurobiologie Hamburg
      Hamburg, Hamburg, Germany
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1983-1999
    • University of California, Berkeley
      • Department of Molecular and Cell Biology
      Berkeley, California, United States
    • Fred Hutchinson Cancer Research Center
      Seattle, Washington, United States
    • University of Oregon
      • Department of Chemistry
      Eugene, Oregon, United States
  • 1994
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
  • 1993
    • Max Planck Institute for Brain Research
      Frankfurt, Hesse, Germany
  • 1990
    • German Cancer Research Center
      Heidelburg, Baden-Württemberg, Germany
    • Georgetown University
      Washington, Washington, D.C., United States
  • 1989
    • Oregon Health and Science University
      • Department of Obstetrics & Gynecology
      Portland, Oregon, United States
  • 1988-1989
    • Heidelberg University
      Tiffin, Ohio, United States
    • Concordia University Texas
      Austin, Texas, United States
  • 1985
    • Salk Institute
      لا هویا, California, United States
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1979
    • University of California, San Francisco
      San Francisco, California, United States
    • City of Hope National Medical Center
      Дуарте, California, United States