Publications by authors named "Peter H Seeburg"

78 Publications

Altered balance of excitatory and inhibitory learning in a genetically modified mouse model of glutamatergic dysfunction relevant to schizophrenia.

Sci Rep 2017 05 11;7(1):1765. Epub 2017 May 11.

Department of Experimental Psychology, University of Oxford, 9 South Parks Road, Oxford, OX1 3UD, UK.

The GluA1 AMPAR subunit (encoded by the Gria1 gene) has been implicated in schizophrenia. Gria1 knockout in mice results in recently experienced stimuli acquiring aberrantly high salience. This suggests that GluA1 may be important for learning that is sensitive to the temporal contiguity between events. To test this, mice were trained on a Pavlovian trace conditioning procedure in which the presentation of an auditory cue and food were separated by a temporal interval. Wild-type mice initially learnt, but with prolonged training came to withhold responding during the trace-conditioned cue, responding less than for another cue that was nonreinforced. Gria1 knockout mice, in contrast, showed sustained performance over training, responding more to the trace-conditioned cue than the nonreinforced cue. Therefore, the trace-conditioned cue acquired inhibitory properties (signalling the absence of food) in wild-type mice, but Gria1 deletion impaired the acquisition of inhibition, thus maintaining the stimulus as an excitatory predictor of food. Furthermore, when there was no trace both groups showed successful learning. These results suggest that cognitive abnormalities in disorders like schizophrenia in which gluatamatergic signalling is implicated may be caused by aberrant salience leading to a change in the nature of the information that is encoded.
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http://dx.doi.org/10.1038/s41598-017-01925-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431791PMC
May 2017

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.

Eur J Neurosci 2017 04 4;45(7):912-921. Epub 2017 Mar 4.

Department of Psychology, Durham University, Science Site, South Road, Durham, DH1 3LE, UK.

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1 mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1 mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.
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http://dx.doi.org/10.1111/ejn.13539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396315PMC
April 2017

Hippocampal GluA1 expression in Gria1 mice only partially restores spatial memory performance deficits.

Neurobiol Learn Mem 2016 Nov 11;135:83-90. Epub 2016 Jul 11.

Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.

Spatial working memory (SWM) is an essential cognitive function important for survival in a competitive environment. In rodents SWM requires an intact hippocampus and SWM expression is impaired in mice lacking the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 (Gria1 mice). Here we used viral gene transfer to show that re-expression of GluA1 in the hippocampus can affect the behavioral performance of GluA1 deficient mice. We found that Gria1 mice with hippocampus-specific rescue of GluA1 expression (Gria1 mice) are more anxious, less hyperactive and only partly impaired in SWM expression in the Y-maze spatial novelty preference paradigm compared to Gria1 mice. However, Gria1 mice still express SWM performance deficits when tested in the rewarded alternation T-maze task. Thus, the restoration of hippocampal function affects several behaviors of GluA1 deficient mice - including SWM expression - in different tasks. The virus-mediated GluA1 expression in Gria1 mice is not sufficient for a comprehensive SWM restoration, suggesting that both hippocampal as well as extra-hippocampal GluA1-containing AMPA receptors contribute to SWM.
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http://dx.doi.org/10.1016/j.nlm.2016.07.005DOI Listing
November 2016

Adenosine-to-inosine RNA editing by ADAR1 is essential for normal murine erythropoiesis.

Exp Hematol 2016 10 1;44(10):947-63. Epub 2016 Jul 1.

St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia. Electronic address:

Adenosine deaminases that act on RNA (ADARs) convert adenosine residues to inosine in double-stranded RNA. In vivo, ADAR1 is essential for the maintenance of hematopoietic stem/progenitors. Whether other hematopoietic cell types also require ADAR1 has not been assessed. Using erythroid- and myeloid-restricted deletion of Adar1, we demonstrate that ADAR1 is dispensable for myelopoiesis but is essential for normal erythropoiesis. Adar1-deficient erythroid cells display a profound activation of innate immune signaling and high levels of cell death. No changes in microRNA levels were found in ADAR1-deficient erythroid cells. Using an editing-deficient allele, we demonstrate that RNA editing is the essential function of ADAR1 during erythropoiesis. Mapping of adenosine-to-inosine editing in purified erythroid cells identified clusters of hyperedited adenosines located in long 3'-untranslated regions of erythroid-specific transcripts and these are ADAR1-specific editing events. ADAR1-mediated RNA editing is essential for normal erythropoiesis.
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http://dx.doi.org/10.1016/j.exphem.2016.06.250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035604PMC
October 2016

Spatially segregated feedforward and feedback neurons support differential odor processing in the lateral entorhinal cortex.

Nat Neurosci 2016 07 16;19(7):935-44. Epub 2016 May 16.

Department of Clinical Neurobiology at the Medical Faculty of Heidelberg University, Heidelberg, Germany.

The lateral entorhinal cortex (LEC) computes and transfers olfactory information from the olfactory bulb to the hippocampus. Here we established LEC connectivity to upstream and downstream brain regions to understand how the LEC processes olfactory information. We report that, in layer II (LII), reelin- and calbindin-positive (RE(+) and CB(+)) neurons constitute two major excitatory cell types that are electrophysiologically distinct and differentially connected. RE(+) neurons convey information to the hippocampus, while CB(+) neurons project to the olfactory cortex and the olfactory bulb. In vivo calcium imaging revealed that RE(+) neurons responded with higher selectivity to specific odors than CB(+) neurons and GABAergic neurons. At the population level, odor discrimination was significantly better for RE(+) than CB(+) neurons, and was lowest for GABAergic neurons. Thus, we identified in LII of the LEC anatomically and functionally distinct neuronal subpopulations that engage differentially in feedforward and feedback signaling during odor processing.
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http://dx.doi.org/10.1038/nn.4303DOI Listing
July 2016

A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

Neuron 2016 Mar 3;89(6):1291-1304. Epub 2016 Mar 3.

Schaller Research Group on Neuropeptides at German Cancer Research Center (DKFZ) and Cell Network Cluster of Excellence at the University of Heidelberg, Heidelberg 69120, Germany; Max Planck Institute for Medical Research, Heidelberg 69120, Germany; Central Institute of Mental Health (ZI), Mannheim 68159, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuron.2016.01.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679079PMC
March 2016

Age-Dependent Degeneration of Mature Dentate Gyrus Granule Cells Following NMDA Receptor Ablation.

Front Mol Neurosci 2015 12;8:87. Epub 2016 Jan 12.

Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg Heidelberg, Germany.

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.
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http://dx.doi.org/10.3389/fnmol.2015.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709453PMC
January 2016

RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.

Science 2015 Sep 23;349(6252):1115-20. Epub 2015 Jul 23.

St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia.

Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) 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), where E861A denotes Glu(861)→Ala(861)). Adar1(E861A/E861A) embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)-sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3' untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of 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.
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http://dx.doi.org/10.1126/science.aac7049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444807PMC
September 2015

Hippocampal synaptic plasticity, spatial memory and anxiety.

Nat Rev Neurosci 2014 03;15(3):181-92

Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany.

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.
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http://dx.doi.org/10.1038/nrn3677DOI Listing
March 2014

Circuit mechanisms of GluA1-dependent spatial working memory.

Hippocampus 2013 Dec 10;23(12):1359-66. Epub 2013 Sep 10.

Laboratory of Neural Circuits and Plasticity, University of Southern California, 3641 Watt Way, Los Angeles, California; Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1002/hipo.22184DOI Listing
December 2013

Homers at the Interface between Reward and Pain.

Front Psychiatry 2013 7;4:39. Epub 2013 Jun 7.

Department of Psychology, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA ; School of Medicine, Pharmacy and Health, Queen's Campus, University of Durham Stockton on Tees, UK.

Pain alters opioid reinforcement, presumably via neuroadaptations within ascending pain pathways interacting with the limbic system. Nerve injury increases expression of glutamate receptors and their associated Homer scaffolding proteins throughout the pain processing pathway. Homer proteins, and their associated glutamate receptors, regulate behavioral sensitivity to various addictive drugs. Thus, we investigated a potential role for Homers in the interactions between pain and drug reward in mice. Chronic constriction injury (CCI) of the sciatic nerve elevated Homer1b/c and/or Homer2a/b expression within all mesolimbic structures examined and for the most part, the Homer increases coincided with elevated mGluR5, GluN2A/B, and the activational state of various 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 small hairpin RNA-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. Together, 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.
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http://dx.doi.org/10.3389/fpsyt.2013.00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675508PMC
July 2013

Differences between RNA and DNA due to RNA editing in temporal lobe epilepsy.

Neurobiol Dis 2013 Aug 20;56:66-73. Epub 2013 Apr 20.

Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany.

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.
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http://dx.doi.org/10.1016/j.nbd.2013.04.006DOI Listing
August 2013

GluA1 and its PDZ-interaction: a role in experience-dependent behavioral plasticity in the forced swim test.

Neurobiol Dis 2013 Apr 20;52:160-7. Epub 2012 Dec 20.

Laboratory of Neural Circuits and Plasticity, University of Southern California, 3641 Watt Way, Los Angeles, CA-90089, USA.

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 are required for the antidepressant-like effects of NMDA receptor antagonists. These findings argue that GluA1-dependent synaptic plasticity might be critically involved in the 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.
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http://dx.doi.org/10.1016/j.nbd.2012.12.003DOI Listing
April 2013

Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion.

Nat Neurosci 2012 Jul 15;15(8):1153-9. Epub 2012 Jul 15.

Department of Experimental Psychology, University of Oxford, Oxford, UK.

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.
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http://dx.doi.org/10.1038/nn.3166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442238PMC
July 2012

A-to-I RNA editing: effects on proteins key to neural excitability.

Neuron 2012 May;74(3):432-9

Institute of Neurobiology and Department of Biochemistry, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico 00901, USA.

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.
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http://dx.doi.org/10.1016/j.neuron.2012.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724421PMC
May 2012

GluA2-lacking AMPA receptors in hippocampal CA1 cell synapses: evidence from gene-targeted mice.

Front Mol Neurosci 2012 24;5:22. Epub 2012 Feb 24.

Division of Neuroscience, Medical Research Institute Ninewells Hospital and Medical School, Dundee University Dundee, UK.

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."
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http://dx.doi.org/10.3389/fnmol.2012.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285882PMC
October 2012

Evoked axonal oxytocin release in the central amygdala attenuates fear response.

Neuron 2012 Feb;73(3):553-66

Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Heidelberg 69120, Germany.

The hypothalamic neuropeptide oxytocin (OT), which controls childbirth and lactation, receives increasing attention for its effects on social behaviors, but how it reaches central brain regions is still unclear. Here we gained by recombinant viruses selective genetic access to hypothalamic OT neurons to study their connectivity and control their activity by optogenetic means. We found axons of hypothalamic OT neurons in the majority of forebrain regions, including the central amygdala (CeA), a structure critically involved in OT-mediated fear suppression. In vitro, exposure to blue light of channelrhodopsin-2-expressing OT axons activated a local GABAergic circuit that inhibited neurons in the output region of the CeA. Remarkably, in vivo, local blue-light-induced endogenous OT release robustly decreased freezing responses in fear-conditioned rats. Our results thus show widespread central projections of hypothalamic OT neurons and demonstrate that OT release from local axonal endings can specifically control region-associated behaviors.
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http://dx.doi.org/10.1016/j.neuron.2011.11.030DOI Listing
February 2012

Dissociations within short-term memory in GluA1 AMPA receptor subunit knockout mice.

Behav Brain Res 2011 Oct 27;224(1):8-14. Epub 2011 May 27.

Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK.

GluA1 AMPA receptor subunit knockout mice display a selective impairment on short-term recognition memory tasks. In this study we tested whether GluA1 is important for short-term memory that is necessary for bridging the discontiguity between cues in trace conditioning. GluA1 knockout mice were not impaired at using short-term memory traces of T-maze floor inserts, made of different materials, to bridge the temporal gap between conditioned stimuli and reinforcement during appetitive discrimination tasks. Thus, different aspects of short-term memory are differentially sensitive to GluA1 deletion. This dissociation may reflect processing of qualitatively different short-term memory traces. Memory that results in performance of short-term recognition (e.g. for objects or places) may be different from the memory required for associative learning in trace conditioning.
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http://dx.doi.org/10.1016/j.bbr.2011.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245382PMC
October 2011

Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice.

J Biol Chem 2011 May 5;286(21):18614-22. Epub 2011 Apr 5.

Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.

ADAR2, an RNA editing enzyme that converts specific adenosines to inosines in certain pre-mRNAs, often leading to amino acid substitutions in the encoded proteins, is mainly expressed in brain. Of all ADAR2-mediated edits, a single one in the pre-mRNA of the AMPA receptor subunit GluA2 is essential for survival. Hence, early postnatal death of mice lacking ADAR2 is averted when the critical edit is engineered into both GluA2 encoding Gria2 alleles. Adar2(-/-)/Gria2(R/R) mice display normal appearance and life span, but the general phenotypic effects of global lack of ADAR2 have remained unexplored. Here we have employed the Adar2(-/-)/Gria2(R/R) mouse line, and Gria2(R/R) mice as controls, to study the phenotypic consequences of loss of all ADAR2-mediated edits except the critical one in GluA2. Our extended phenotypic analysis covering ∼320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.
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http://dx.doi.org/10.1074/jbc.M110.200881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3099677PMC
May 2011

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice.

J Clin Invest 2011 Apr 7;121(4):1608-23. Epub 2011 Mar 7.

Institute for Pharmacology, Heidelberg University, Heidelberg, Germany.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA-type) glutamate receptors (AMPARs) play an important role in plasticity at central synapses. Although there is anatomical evidence for AMPAR expression in the peripheral nervous system, the functional role of such receptors in vivo is not clear. To address this issue, we generated mice specifically lacking either of the key AMPAR subunits, GluA1 or GluA2, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system. Nociceptor-specific deletion of GluA1 led to disruption of calcium permeability and reduced capsaicin-evoked activation of nociceptors. Deletion of GluA1, but not GluA2, led to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. Further analysis revealed that GluA1-containing AMPARs regulated the responses of nociceptors to painful stimuli in inflamed tissues and controlled the excitatory drive from the periphery into the spinal cord. Consequently, peripherally applied AMPAR antagonists alleviated inflammatory pain by specifically blocking calcium-permeable AMPARs, without affecting physiological pain or eliciting central side effects. These findings indicate an important pathophysiological role for calcium-permeable AMPARs in nociceptors and may have therapeutic implications for the treatment chronic inflammatory pain states.
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http://dx.doi.org/10.1172/JCI44911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069784PMC
April 2011

Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory.

Learn Mem 2011 4;18(3):181-90. Epub 2011 Mar 4.

Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, United Kingdom.

Deletion of the GluA1 AMPA receptor subunit impairs short-term spatial recognition memory. It has been suggested that short-term recognition depends upon memory caused by the recent presentation of a stimulus that is independent of contextual-retrieval processes. The aim of the present set of experiments was to test whether the role of GluA1 extends to nonspatial recognition memory. Wild-type and GluA1 knockout mice were tested on the standard object recognition task and a context-independent recognition task that required recency-dependent memory. In a first set of experiments it was found that GluA1 deletion failed to impair performance on either of the object recognition or recency-dependent tasks. However, GluA1 knockout mice displayed increased levels of exploration of the objects in both the sample and test phases compared to controls. In contrast, when the time that GluA1 knockout mice spent exploring the objects was yoked to control mice during the sample phase, it was found that GluA1 deletion now impaired performance on both the object recognition and the recency-dependent tasks. GluA1 deletion failed to impair performance on a context-dependent recognition task regardless of whether object exposure in knockout mice was yoked to controls or not. These results demonstrate that GluA1 is necessary for nonspatial as well as spatial recognition memory and plays an important role in recency-dependent memory processes.
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http://dx.doi.org/10.1101/lm.2083411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056514PMC
July 2011

Deletion of the GluA1 AMPA receptor subunit alters the expression of short-term memory.

Learn Mem 2011 Mar 16;18(3):128-31. Epub 2011 Feb 16.

Department of Experimental Psychology, University of Oxford, Oxford OX1 3UD, United Kingdom.

Deletion of the GluA1 AMPA receptor subunit selectively impairs short-term memory for spatial locations. We further investigated this deficit by examining memory for discrete nonspatial visual stimuli in an operant chamber. Unconditioned suppression of magazine responding to visual stimuli was measured in wild-type and GluA1 knockout mice. Wild-type mice showed less suppression to a stimulus that had been presented recently than to a stimulus that had not. GluA1 knockout mice, however, showed greater suppression to a recent stimulus than to a nonrecent stimulus. Thus, GluA1 is not necessary for encoding, but affects the way that short-term memory is expressed.
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http://dx.doi.org/10.1101/lm.2014911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056516PMC
March 2011

Homeostatic scaling requires group I mGluR activation mediated by Homer1a.

Neuron 2010 Dec;68(6):1128-42

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Homeostatic scaling is a non-Hebbian form of neural plasticity that maintains neuronal excitability and informational content of synaptic arrays in the face of changes of network activity. Here, we demonstrate that homeostatic scaling is dependent on group I metabotropic glutamate receptor activation that is mediated by the immediate early gene Homer1a. Homer1a is transiently upregulated during increases in network activity and evokes agonist-independent signaling of group I mGluRs that scales down the expression of synaptic AMPA receptors. Homer1a effects are dynamic and play a role in the induction of scaling. Similar to mGluR-LTD, Homer1a-dependent scaling involves a reduction of tyrosine phosphorylation of GluA2 (GluR2), but is distinct in that it exploits a unique signaling property of group I mGluR to confer cell-wide, agonist-independent activation of the receptor. These studies reveal an elegant interplay of mechanisms that underlie Hebbian and non-Hebbian plasticity.
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http://dx.doi.org/10.1016/j.neuron.2010.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013614PMC
December 2010

Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2.

J Neurosci 2010 Sep;30(36):11917-25

Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, University of Tokyo, Bunkyo-ku, Tokyo, Japan.

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca(2+) permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.2021-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633551PMC
September 2010

Spatial working memory deficits in GluA1 AMPA receptor subunit knockout mice reflect impaired short-term habituation: evidence for Wagner's dual-process memory model.

Neuropsychologia 2010 Jul 27;48(8):2303-15. Epub 2010 Mar 27.

Department of Experimental Psychology, University of Oxford, Oxford, UK.

Genetically modified mice, lacking the GluA1 AMPA receptor subunit, are impaired on spatial working memory tasks, but display normal acquisition of spatial reference memory tasks. One explanation for this dissociation is that working memory, win-shift performance engages a GluA1-dependent, non-associative, short-term memory process through which animals choose relatively novel arms in preference to relatively familiar options. In contrast, spatial reference memory, as exemplified by the Morris water maze task, reflects a GluA1-independent, associative, long-term memory mechanism. These results can be accommodated by Wagner's dual-process model of memory in which short and long-term memory mechanisms exist in parallel and, under certain circumstances, compete with each other. According to our analysis, GluA1(-/-) mice lack short-term memory for recently experienced spatial stimuli. One consequence of this impairment is that these stimuli should remain surprising and thus be better able to form long-term associative representations. Consistent with this hypothesis, we have recently shown that long-term spatial memory for recently visited locations is enhanced in GluA1(-/-) mice, despite impairments in hippocampal synaptic plasticity. Taken together, these results support a role for GluA1-containing AMPA receptors in short-term habituation, and in modulating the intensity or perceived salience of stimuli.
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http://dx.doi.org/10.1016/j.neuropsychologia.2010.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938569PMC
July 2010

CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus.

Science 2010 Mar 25;327(5972):1518-22. Epub 2010 Feb 25.

Department of Clinical Neurobiology, University of Heidelberg, 6910 Heidelberg, Germany.

CKAMP44, identified here by a proteomic approach, is a brain-specific type I transmembrane protein that associates with AMPA receptors in synaptic spines. CKAMP44 expressed in Xenopus oocytes reduced GluA1- and A2-mediated steady-state currents, but did not affect kainate- or N-methyl-D-aspartate (NMDA) receptor-mediated currents. Mouse hippocampal CA1 pyramidal neurons expressed CKAMP44 at low abundance, and overexpression of CKAMP44 led to stronger and faster AMPA receptor desensitization, slower recovery from desensitization, and a reduction in the paired-pulse ratio of AMPA currents. By contrast, dentate gyrus granule cells exhibited strong CKAMP44 expression, and CKAMP44 knockout increased the paired-pulse ratio of AMPA currents in lateral and medial perforant path-granule cell synapses. CKAMP44 thus modulates short-term plasticity at specific excitatory synapses.
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http://dx.doi.org/10.1126/science.1184178DOI Listing
March 2010

Synaptic inhibition in the olfactory bulb accelerates odor discrimination in mice.

Neuron 2010 Feb;65(3):399-411

Institute of Anatomy and Cell Biology, University of Heidelberg, INF 307, 69120 Heidelberg, Germany; WIN Olfactory Dynamics Group, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany.

Local inhibitory circuits are thought to shape neuronal information processing in the central nervous system, but it remains unclear how specific properties of inhibitory neuronal interactions translate into behavioral performance. In the olfactory bulb, inhibition of mitral/tufted cells via granule cells may contribute to odor discrimination behavior by refining neuronal representations of odors. Here we show that selective deletion of the AMPA receptor subunit GluA2 in granule cells boosted synaptic Ca(2+) influx, increasing inhibition of mitral cells. On a behavioral level, discrimination of similar odor mixtures was accelerated while leaving learning and memory unaffected. In contrast, selective removal of NMDA receptors in granule cells slowed discrimination of similar odors. Our results demonstrate that inhibition of mitral cells controlled by granule cell glutamate receptors results in fast and accurate discrimination of similar odors. Thus, spatiotemporally defined molecular perturbations of olfactory bulb granule cells directly link stimulus similarity, neuronal processing time, and discrimination behavior to synaptic inhibition.
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http://dx.doi.org/10.1016/j.neuron.2010.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366558PMC
February 2010

Synaptic NR2A- but not NR2B-Containing NMDA Receptors Increase with Blockade of Ionotropic Glutamate Receptors.

Front Mol Neurosci 2009 26;2:19. Epub 2009 Oct 26.

Department of Clinical Neurobiology, University of Heidelberg Heidelberg, Germany.

NMDA receptors (NMDAR) are key molecules involved in physiological and pathophysiological brain processes such as plasticity and excitotoxicity. Neuronal activity regulates NMDA receptor levels in the cell membrane. However, little is known on which time scale this regulation occurs and whether the two main diheteromeric NMDA receptor subtypes in forebrain, NR1/NR2A and NR1/NR2B, are regulated in a similar fashion. As these differ considerably in their electrophysiological properties, the NR2A/NR2B ratio affects the neurons' reaction to NMDA receptor activation. Here we provide evidence that the basal turnover rate in the cell membrane of NR2A- and NR2B-containing receptors is comparable. However, the level of the NR2A subtype in the cell membrane is highly regulated by NMDA receptor activity, resulting in a several-fold increased insertion of new receptors after blocking NMDAR for 8 h. Blocking AMPA receptors also increases the delivery of NR2A-containing receptors to the cell membrane. In contrast, the amount of NR2B-containing receptors in the cell membrane is not affected by ionotropic glutamate receptor block. Moreover, electrophysiological analysis of synaptic currents in hippocampal cultures and CA1 neurons of hippocampal slices revealed that after 8 h of NMDA receptor blockade the NMDA EPSCs increase as a result of augmented NMDA receptor-mediated currents. In conclusion, synaptic NR2A- but not NR2B-containing receptors are dynamically regulated, enabling neurons to change their NR2A/NR2B ratio within a time scale of hours.
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http://dx.doi.org/10.3389/neuro.02.019.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773170PMC
July 2011

Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion.

Eur J Pharmacol 2010 Jan 15;626(1):49-56. Epub 2009 Oct 15.

Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK.

David De Wied had a fundamental interest in the brain and behaviour, with a particular interest in the interface between cognition and emotion, and how impairments at this interface could underlie human psychopathology. The NMDA subtype of glutamate receptor is an important mediator of synaptic plasticity and plays a central role in the neurobiological mechanisms of emotionality, as well as learning and memory. NMDA receptor antagonists affect various aspects of emotionality including fear, anxiety and depression, as well as impairing certain forms of learning and memory. The hippocampus is a key brain structure, implicated in both cognition and emotion. Lesion studies in animals have suggested that dorsal and ventral sub-regions of the hippocampus are differentially involved in dissociable aspects of hippocampus-dependent behaviour. Cytotoxic lesions of the dorsal hippocampus (septal pole) in rodents impair spatial learning but have no effect on anxiety, whereas ventral hippocampal lesions reduce anxiety but are without effect on spatial memory. This role for the ventral hippocampus in anxiety is distinct from the role of the amygdala in other aspects of emotional processing, such as fear conditioning. Recent studies with genetically modified mice have shown that NR1 NMDA receptor subunit deletion, specifically from the granule cells of the dentate gyrus, not only impairs short-term spatial memory but also reduces anxiety. This suggests that NMDA receptors in ventral hippocampus may be a key locus supporting the anxiolytic effects of NMDA receptor antagonists. These data support Gray's neuropsychological account of hippocampal function.
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http://dx.doi.org/10.1016/j.ejphar.2009.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824088PMC
January 2010

Major signaling pathways in migrating neuroblasts.

Front Mol Neurosci 2009 24;2. Epub 2009 Jul 24.

Department of Clinical Neurobiology, Interdisciplinary Center for Neurosciences Heidelberg, Germany.

Neuronal migration is a key process in the developing and adult brain. Numerous factors act on intracellular cascades of migrating neurons and regulate the final position of neurons. One robust migration route persists postnatally - the rostral migratory stream (RMS). To identify genes that govern neuronal migration in this unique structure, we isolated RMS neuroblasts by making use of transgenic mice that express EGFP in this cell population and performed microarray analysis on RNA. We compared gene expression patterns of neuroblasts obtained from two sites of the RMS, one closer to the site of origin, the subventricular zone, and one closer to the site of the final destination, the olfactory bulb (OB). We identified more than 400 upregulated genes, many of which were not known to be involved in migration. These genes were grouped into functional networks by bioinformatics analysis. Selecting a specific upregulated intracellular network, the cytoskeleton pathway, we confirmed by functional in vitro and in vivo analysis that the identified genes of this network affected RMS neuroblast migration. Based on the validity of this approach, we chose four new networks and tested by functional in vivo analysis their involvement in neuroblast migration. Thus, knockdown of Calm1, Gria1 (GluA1) and Camk4 (calmodulin-signaling network), Hdac2 and Hsbp1 (Akt1-DNA transcription network), Vav3 and Ppm1a (growth factor signaling network) affected neuroblast migration to the OB.
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http://dx.doi.org/10.3389/neuro.02.007.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724029PMC
July 2011