Publications by authors named "Jack R Mellor"

44 Publications

Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits.

PLoS Comput Biol 2021 Oct 1;17(10):e1009435. Epub 2021 Oct 1.

Centre for Synaptic Plasticity, School of Physiology Pharmacology, and Neuroscience, University of Bristol, Bristol, United Kingdom.

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory-Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.
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http://dx.doi.org/10.1371/journal.pcbi.1009435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513881PMC
October 2021

Sustained postsynaptic kainate receptor activation downregulates AMPA receptor surface expression and induces hippocampal LTD.

iScience 2021 Sep 25;24(9):103029. Epub 2021 Aug 25.

Centre for Synaptic Plasticity, School of Biochemistry, Centre for Synaptic Plasticity, Biomedical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.

It is well established that long-term depression (LTD) can be initiated by either NMDA or mGluR activation. Here we report that sustained activation of GluK2 subunit-containing kainate receptors (KARs) leads to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) endocytosis and induces LTD of AMPARs (KAR-LTD) in hippocampal neurons. The KAR-evoked loss of surface AMPARs is blocked by the ionotropic KAR inhibitor UBP 310 indicating that KAR-LTD requires KAR channel activity. Interestingly, however, blockade of PKC or PKA also reduces GluA2 surface expression and occludes the effect of KAR activation. In acute hippocampal slices, kainate application caused a significant loss of GluA2-containing AMPARs from synapses and long-lasting depression of AMPAR excitatory postsynaptic currents in CA1. These data, together with our previously reported KAR-LTP, demonstrate that KARs can bidirectionally regulate synaptic AMPARs and synaptic plasticity via different signaling pathways.
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http://dx.doi.org/10.1016/j.isci.2021.103029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441151PMC
September 2021

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits.

Nat Commun 2021 09 16;12(1):5475. Epub 2021 Sep 16.

Center for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol, UK.

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M and M receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.
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http://dx.doi.org/10.1038/s41467-021-25280-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445995PMC
September 2021

21st century excitatory amino acid research: A Q & A with Jeff Watkins and Dick Evans.

Neuropharmacology 2021 10 5;198:108743. Epub 2021 Aug 5.

School of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK. Electronic address:

In 1981 Jeff Watkins and Dick Evans wrote what was to become a seminal review on excitatory amino acids (EAAs) and their receptors (Watkins and Evans, 1981). Bringing together various lines of evidence dating back over several decades on: the distribution in the nervous system of putative amino acid neurotransmitters; enzymes involved in their production and metabolism; the uptake and release of amino acids; binding of EAAs to membranes; the pharmacological action of endogenous excitatory amino acids and their synthetic analogues, and notably the actions of antagonists for the excitations caused by both nerve stimulation and exogenous agonists, often using pharmacological tools developed by Jeff and his colleagues, they provided a compelling account for EAAs, especially l-glutamate, as a bona fide neurotransmitter in the nervous system. The rest, as they say, is history, but far from being consigned to history, EAA research is in rude health well into the 21st Century as this series of Special Issues of Neuropharmacology exemplifies. With EAAs and their receptors flourishing across a wide range of disciplines and clinical conditions, we enter into a dialogue with two of the most prominent and influential figures in the early days of EAA research: Jeff Watkins and Dick Evans.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108743DOI Listing
October 2021

Kainate receptors and synaptic plasticity.

Neuropharmacology 2021 09 30;196:108540. Epub 2021 Mar 30.

Center for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol, BS8 1TD, UK. Electronic address:

Synaptic plasticity has classically been characterized to involve the NMDA and AMPA subtypes of glutamate receptors, with NMDA receptors providing the key trigger for the induction of long-term plasticity leading to changes in AMPA receptor expression. Here we review the more subtle roles played by kainate receptors, which contribute critical postsynaptic signalling as well as playing major presynaptic auto-receptor roles. We focus on two research areas: plasticity of kainate receptors themselves and the contribution they make to the plasticity of synaptic transmission. This article is part of the special issue on Glutamate Receptors - Kainate receptors.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108540DOI Listing
September 2021

Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output.

Nat Commun 2020 09 2;11(1):4395. Epub 2020 Sep 2.

Center for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol, BS8 1TD, UK.

The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.
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http://dx.doi.org/10.1038/s41467-020-18074-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467931PMC
September 2020

Noradrenaline Release from Locus Coeruleus Terminals in the Hippocampus Enhances Excitation-Spike Coupling in CA1 Pyramidal Neurons Via β-Adrenoceptors.

Cereb Cortex 2020 11;30(12):6135-6151

Centre for Synaptic Plasticity, University of Bristol, Bristol, UK.

Release of the neuromodulator noradrenaline signals salience during wakefulness, flagging novel or important experiences to reconfigure information processing and memory representations in the hippocampus. Noradrenaline is therefore expected to enhance hippocampal responses to synaptic input; however, noradrenergic agonists have been found to have mixed and sometimes contradictory effects on Schaffer collateral synapses and the resulting CA1 output. Here, we examine the effects of endogenous, optogenetically driven noradrenaline release on synaptic transmission and spike output in mouse hippocampal CA1 pyramidal neurons. We show that endogenous noradrenaline release enhances the probability of CA1 pyramidal neuron spiking without altering feedforward excitatory or inhibitory synaptic inputs in the Schaffer collateral pathway. β-adrenoceptors mediate this enhancement of excitation-spike coupling by reducing the charge required to initiate action potentials, consistent with noradrenergic modulation of voltage-gated potassium channels. Furthermore, we find the likely effective concentration of endogenously released noradrenaline is sub-micromolar. Surprisingly, although comparable concentrations of exogenous noradrenaline cause robust depression of slow afterhyperpolarization currents, endogenous release of noradrenaline does not, indicating that endogenous noradrenaline release is targeted to specific cellular locations. These findings provide a mechanism by which targeted endogenous release of noradrenaline can enhance information transfer in the hippocampus in response to salient events.
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http://dx.doi.org/10.1093/cercor/bhaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609922PMC
November 2020

Comparison of acute treatment with delayed-onset versus rapid-acting antidepressants on effort-related choice behaviour.

Psychopharmacology (Berl) 2020 Aug 20;237(8):2381-2394. Epub 2020 May 20.

School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK.

Rationale: Reward-related impairments are common in major depressive disorder (MDD) and may contribute to the loss of interest in pleasurable activities. A novel approach to studying reward-related decision-making are effort-based tasks; however, direct comparisons between delayed-onset and rapid-acting antidepressants (ADs) have not yet been carried out.

Objectives: To investigate the effects of conventional delayed-onset ADs versus rapid-acting ADs, ketamine and scopolamine, on effort-related choice behaviour.

Methods: Female Lister hooded rats were trained in an operant effort for reward task (EfRT) where animals choose between working for a high value-high effort reward and consuming low value-low effort chow. Using a within-subject study design, animals were then tested following acute treatment with different monoaminergic ADs, and the rapid-acting ADs ketamine or scopolamine.

Results: Consistent with previous findings, we found choice behaviour was sensitive to dopaminergic manipulations. We observed that pre-feeding altered choice behaviour and that the use of high or low value reward differentially affected behaviour. Monoamine re-uptake inhibitors and rapid-acting ADs resulted in similar, general patterns of reduced motivation without any evidence for specific effects, and we did not observe any clear differences between these classes of antidepressant.

Conclusions: Motivational changes induced by dopaminergic manipulations and pre-feeding differentially affect effort choice behaviour. However, both conventional delayed-onset ADs and ketamine and scopolamine appear to have detrimental effects on motivation in this task at the higher doses tested without any evidence of specificity for effort-related choice behaviour, in contrast to their specificity in tasks which look at more cognitive aspects of reward processing.
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http://dx.doi.org/10.1007/s00213-020-05541-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351874PMC
August 2020

Comparison of conventional and rapid-acting antidepressants in a rodent probabilistic reversal learning task.

Brain Neurosci Adv 2020 Jan-Dec;4:2398212820907177. Epub 2020 Feb 23.

School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.

Deficits in reward processing are a central feature of major depressive disorder with patients exhibiting decreased reward learning and altered feedback sensitivity in probabilistic reversal learning tasks. Methods to quantify probabilistic learning in both rodents and humans have been developed, providing translational paradigms for depression research. We have utilised a probabilistic reversal learning task to investigate potential differences between conventional and rapid-acting antidepressants on reward learning and feedback sensitivity. We trained 12 rats in a touchscreen probabilistic reversal learning task before investigating the effect of acute administration of citalopram, venlafaxine, reboxetine, ketamine or scopolamine. Data were also analysed using a Q-learning reinforcement learning model to understand the effects of antidepressant treatment on underlying reward processing parameters. Citalopram administration decreased trials taken to learn the first rule and increased win-stay probability. Reboxetine decreased win-stay behaviour while also decreasing the number of rule changes animals performed in a session. Venlafaxine had no effect. Ketamine and scopolamine both decreased win-stay probability, number of rule changes performed and motivation in the task. Insights from the reinforcement learning model suggested that reboxetine led animals to choose a less optimal strategy, while ketamine decreased the model-free learning rate. These results suggest that reward learning and feedback sensitivity are not differentially modulated by conventional and rapid-acting antidepressant treatment in the probabilistic reversal learning task.
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http://dx.doi.org/10.1177/2398212820907177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085917PMC
February 2020

A Bayesian predictive approach for dealing with pseudoreplication.

Sci Rep 2020 02 11;10(1):2366. Epub 2020 Feb 11.

MRC Integrative Epidemiology Unit, UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, BS8 1TU, UK.

Pseudoreplication occurs when the number of measured values or data points exceeds the number of genuine replicates, and when the statistical analysis treats all data points as independent and thus fully contributing to the result. By artificially inflating the sample size, pseudoreplication contributes to irreproducibility, and it is a pervasive problem in biological research. In some fields, more than half of published experiments have pseudoreplication - making it one of the biggest threats to inferential validity. Researchers may be reluctant to use appropriate statistical methods if their hypothesis is about the pseudoreplicates and not the genuine replicates; for example, when an intervention is applied to pregnant female rodents (genuine replicates) but the hypothesis is about the effect on the multiple offspring (pseudoreplicates). We propose using a Bayesian predictive approach, which enables researchers to make valid inferences about biological entities of interest, even if they are pseudoreplicates, and show the benefits of this approach using two in vivo data sets.
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http://dx.doi.org/10.1038/s41598-020-59384-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012913PMC
February 2020

Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus.

J Neurosci 2018 10 21;38(43):9252-9262. Epub 2018 Sep 21.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, United Kingdom and

Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits. Memory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.
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http://dx.doi.org/10.1523/JNEUROSCI.1160-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199408PMC
October 2018

Neuromodulation of hippocampal long-term synaptic plasticity.

Curr Opin Neurobiol 2019 02 10;54:37-43. Epub 2018 Sep 10.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK. Electronic address:

Multiple neuromodulators including acetylcholine, noradrenaline, dopamine and serotonin are released in response to uncertainty to focus attention on events where the predicted outcome does not match observed reality. In these situations, internal representations need to be updated, a process that requires long-term synaptic plasticity. Through a variety of common and divergent mechanisms, it is recently shown that all these neuromodulators facilitate the induction and/or expression of long-term synaptic plasticity within the hippocampus. Under physiological conditions, this may be critical for suprathreshold induction of plasticity endowing neuromodulators with a gating function and providing a mechanism by which neuromodulators enable the targeted updating of memory with relevant information to improve the accuracy of future predictions.
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http://dx.doi.org/10.1016/j.conb.2018.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367596PMC
February 2019

Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit.

Sci Rep 2018 03 7;8(1):4155. Epub 2018 Mar 7.

Centre for Synaptic Plasticity and School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, BS8, 1TD, UK.

AMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression.
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http://dx.doi.org/10.1038/s41598-018-22542-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841360PMC
March 2018

Acetylcholine modulates gamma frequency oscillations in the hippocampus by activation of muscarinic M1 receptors.

Eur J Neurosci 2017 06 8;45(12):1570-1585. Epub 2017 May 8.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK.

Modulation of gamma oscillations is important for the processing of information and the disruption of gamma oscillations is a prominent feature of schizophrenia and Alzheimer's disease. Gamma oscillations are generated by the interaction of excitatory and inhibitory neurons where their precise frequency and amplitude are controlled by the balance of excitation and inhibition. Acetylcholine enhances the intrinsic excitability of pyramidal neurons and suppresses both excitatory and inhibitory synaptic transmission, but the net modulatory effect on gamma oscillations is not known. Here, we find that the power, but not frequency, of optogenetically induced gamma oscillations in the CA3 region of mouse hippocampal slices is enhanced by low concentrations of the broad-spectrum cholinergic agonist carbachol but reduced at higher concentrations. This bidirectional modulation of gamma oscillations is replicated within a mathematical model by neuronal depolarisation, but not by reducing synaptic conductances, mimicking the effects of muscarinic M1 receptor activation. The predicted role for M1 receptors was supported experimentally; bidirectional modulation of gamma oscillations by acetylcholine was replicated by a selective M1 receptor agonist and prevented by genetic deletion of M1 receptors. These results reveal that acetylcholine release in CA3 of the hippocampus modulates gamma oscillation power but not frequency in a bidirectional and dose-dependent manner by acting primarily through muscarinic M1 receptors.
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http://dx.doi.org/10.1111/ejn.13582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518221PMC
June 2017

Coordinated Acetylcholine Release in Prefrontal Cortex and Hippocampus Is Associated with Arousal and Reward on Distinct Timescales.

Cell Rep 2017 01;18(4):905-917

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK. Electronic address:

Cholinergic neurotransmission throughout the neocortex and hippocampus regulates arousal, learning, and attention. However, owing to the poorly characterized timing and location of acetylcholine release, its detailed behavioral functions remain unclear. Using electrochemical biosensors chronically implanted in mice, we made continuous measurements of the spatiotemporal dynamics of acetylcholine release across multiple behavioral states. We found that tonic levels of acetylcholine release were coordinated between the prefrontal cortex and hippocampus and maximal during training on a rewarded working memory task. Tonic release also increased during REM sleep but was contingent on subsequent wakefulness. In contrast, coordinated phasic acetylcholine release occurred only during the memory task and was strongly localized to reward delivery areas without being contingent on trial outcome. These results show that coordinated acetylcholine release between the prefrontal cortex and hippocampus is associated with reward and arousal on distinct timescales, providing dual mechanisms to support learned behavior acquisition during cognitive task performance.
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http://dx.doi.org/10.1016/j.celrep.2016.12.085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289927PMC
January 2017

Neuromodulation of the Feedforward Dentate Gyrus-CA3 Microcircuit.

Front Synaptic Neurosci 2016 17;8:32. Epub 2016 Oct 17.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol Bristol, UK.

The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval.
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http://dx.doi.org/10.3389/fnsyn.2016.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065980PMC
October 2016

Assessment of Methods for the Intracellular Blockade of GABAA Receptors.

PLoS One 2016 8;11(8):e0160900. Epub 2016 Aug 8.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, United Kingdom.

Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4'-dinitro-stilbene-2,2'-disulphonic acid (DNDS) and 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160900PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976935PMC
August 2017

Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines.

PLoS Comput Biol 2016 05 27;12(5):e1004949. Epub 2016 May 27.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom.

The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators.
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http://dx.doi.org/10.1371/journal.pcbi.1004949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883788PMC
May 2016

Sharp-Wave Ripples Orchestrate the Induction of Synaptic Plasticity during Reactivation of Place Cell Firing Patterns in the Hippocampus.

Cell Rep 2016 Mar 18;14(8):1916-29. Epub 2016 Feb 18.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK. Electronic address:

Place cell firing patterns reactivated during hippocampal sharp-wave ripples (SWRs) in rest or sleep are thought to induce synaptic plasticity and thereby promote the consolidation of recently encoded information. However, the capacity of reactivated spike trains to induce plasticity has not been directly tested. Here, we show that reactivated place cell firing patterns simultaneously recorded from CA3 and CA1 of rat dorsal hippocampus are able to induce long-term potentiation (LTP) at synapses between CA3 and CA1 cells but only if accompanied by SWR-associated synaptic activity and resulting dendritic depolarization. In addition, we show that the precise timing of coincident CA3 and CA1 place cell spikes in relation to SWR onset is critical for the induction of LTP and predictive of plasticity generated by reactivation. Our findings confirm an important role for SWRs in triggering and tuning plasticity processes that underlie memory consolidation in the hippocampus during rest or sleep.
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http://dx.doi.org/10.1016/j.celrep.2016.01.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785795PMC
March 2016

Coordinated activation of distinct Ca(2+) sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity.

Nat Commun 2016 Jan 13;7:10289. Epub 2016 Jan 13.

Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK.

At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage-sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function.
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http://dx.doi.org/10.1038/ncomms10289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735496PMC
January 2016

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.

Cereb Cortex 2016 Jan 15;26(1):414-26. Epub 2015 Oct 15.

School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function. We confirm that M1R activation increases input resistance and depolarizes hippocampal CA1 pyramidal neurons and show that this profoundly increases excitatory postsynaptic potential-spike coupling. Consistent with a critical role for M1Rs in synaptic plasticity, we now show that M1R activation produces a robust potentiation of glutamatergic synaptic transmission onto CA1 pyramidal neurons that has all the hallmarks of long-term potentiation (LTP): The potentiation requires NMDA receptor activity and bi-directionally occludes with synaptically induced LTP. Thus, we describe synergistic mechanisms by which acetylcholine acting through M1Rs excites CA1 pyramidal neurons and induces LTP, to profoundly increase activation of CA1 pyramidal neurons. These features are predicted to make a major contribution to the pro-cognitive effects of cholinergic transmission in rodents and humans.
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http://dx.doi.org/10.1093/cercor/bhv227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677984PMC
January 2016

Memory trace replay: the shaping of memory consolidation by neuromodulation.

Trends Neurosci 2015 Sep 11;38(9):560-70. Epub 2015 Aug 11.

School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.

The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed.
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http://dx.doi.org/10.1016/j.tins.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712256PMC
September 2015

Clathrin-independent trafficking of AMPA receptors.

J Neurosci 2015 Mar;35(12):4830-6

Schools of Biochemistry and

Membrane trafficking of AMPA receptors (AMPARs) is critical for neuronal function and plasticity. Although rapid forms of AMPAR internalization during long-term depression (LTD) require clathrin and dynamin, the mechanisms governing constitutive AMPAR turnover and internalization of AMPARs during slow homeostatic forms of synaptic plasticity remain unexplored. Here, we show that, in contrast to LTD, constitutive AMPAR internalization and homeostatic AMPAR downscaling in rat neurons do not require dynamin or clathrin function. Instead, constitutive AMPAR trafficking is blocked by a Rac1 inhibitor and is regulated by a dynamic nonstructural pool of F-actin. Our findings reveal a novel role for neuronal clathrin-independent endocytosis controlled by actin dynamics and suggest that the interplay between different modes of receptor endocytosis provides for segregation between distinct modes of neuronal plasticity.
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http://dx.doi.org/10.1523/JNEUROSCI.3571-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389590PMC
March 2015

Cholinergic modulation of hippocampal network function.

Front Synaptic Neurosci 2013 30;5. Epub 2013 Jul 30.

Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, University Walk Bristol, UK.

Cholinergic septohippocampal projections from the medial septal area to the hippocampus are proposed to have important roles in cognition by modulating properties of the hippocampal network. However, the precise spatial and temporal profile of acetylcholine release in the hippocampus remains unclear making it difficult to define specific roles for cholinergic transmission in hippocampal dependent behaviors. This is partly due to a lack of tools enabling specific intervention in, and recording of, cholinergic transmission. Here, we review the organization of septohippocampal cholinergic projections and hippocampal acetylcholine receptors as well as the role of cholinergic transmission in modulating cellular excitability, synaptic plasticity, and rhythmic network oscillations. We point to a number of open questions that remain unanswered and discuss the potential for recently developed techniques to provide a radical reappraisal of the function of cholinergic inputs to the hippocampus.
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http://dx.doi.org/10.3389/fnsyn.2013.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726829PMC
August 2013

The small GTPase Arf1 modulates Arp2/3-mediated actin polymerization via PICK1 to regulate synaptic plasticity.

Neuron 2013 Jul;79(2):293-307

School of Biochemistry, Centre for Synaptic Plasticity, Medical Sciences Building and Dorothy Hodgkin Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.

Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.
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http://dx.doi.org/10.1016/j.neuron.2013.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725416PMC
July 2013

Long-term depression of synaptic kainate receptors reduces excitability by relieving inhibition of the slow afterhyperpolarization.

J Neurosci 2013 May;33(22):9536-45

MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.

Kainate receptors (KARs) are ionotropic glutamate receptors that also activate noncanonical G-protein-coupled signaling pathways to depress the slow afterhyperpolarization (sAHP). Here we show that long-term depression of KAR-mediated synaptic transmission (KAR LTD) at rat hippocampal mossy fiber synapses relieves inhibition of the sAHP by synaptic transmission. KAR LTD is induced by high-frequency mossy fiber stimulation and natural spike patterns and requires activation of adenosine A2A receptors. Natural spike patterns also cause long-term potentiation of NMDA receptor-mediated synaptic transmission that overrides the effects of KAR LTD on the cellular response to low-frequency synaptic input. However, KAR LTD is dominant at higher frequency synaptic stimulation where it decreases the cellular response by relieving inhibition of the sAHP. Thus we describe a form of glutamate receptor plasticity induced by natural spike patterns whose primary physiological function is to regulate cellular excitability.
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http://dx.doi.org/10.1523/JNEUROSCI.0034-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223608PMC
May 2013

Wavelet transform-based de-noising for two-photon imaging of synaptic Ca2+ transients.

Biophys J 2013 Mar;104(5):1006-17

Medical Research Council Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.

Postsynaptic Ca(2+) transients triggered by neurotransmission at excitatory synapses are a key signaling step for the induction of synaptic plasticity and are typically recorded in tissue slices using two-photon fluorescence imaging with Ca(2+)-sensitive dyes. The signals generated are small with very low peak signal/noise ratios (pSNRs) that make detailed analysis problematic. Here, we implement a wavelet-based de-noising algorithm (PURE-LET) to enhance signal/noise ratio for Ca(2+) fluorescence transients evoked by single synaptic events under physiological conditions. Using simulated Ca(2+) transients with defined noise levels, we analyzed the ability of the PURE-LET algorithm to retrieve the underlying signal. Fitting single Ca(2+) transients with an exponential rise and decay model revealed a distortion of τ(rise) but improved accuracy and reliability of τ(decay) and peak amplitude after PURE-LET de-noising compared to raw signals. The PURE-LET de-noising algorithm also provided a ∼30-dB gain in pSNR compared to ∼16-dB pSNR gain after an optimized binomial filter. The higher pSNR provided by PURE-LET de-noising increased discrimination accuracy between successes and failures of synaptic transmission as measured by the occurrence of synaptic Ca(2+) transients by ∼20% relative to an optimized binomial filter. Furthermore, in comparison to binomial filter, no optimization of PURE-LET de-noising was required for reducing arbitrary bias. In conclusion, the de-noising of fluorescent Ca(2+) transients using PURE-LET enhances detection and characterization of Ca(2+) responses at central excitatory synapses.
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http://dx.doi.org/10.1016/j.bpj.2013.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607703PMC
March 2013

Putting plasticity in its place.

Front Neurosci 2012 13;6:110. Epub 2012 Jul 13.

MRC Centre for Synaptic Plasticity, School of Physiological and Pharmacology, University of Bristol Bristol, UK.

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http://dx.doi.org/10.3389/fnins.2012.00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395797PMC
October 2012

Homeostatic synaptic scaling is regulated by protein SUMOylation.

J Biol Chem 2012 Jun 11;287(27):22781-8. Epub 2012 May 11.

Medical Research Council Centre for Synaptic Plasticity, School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom.

Homeostatic scaling allows neurons to alter synaptic transmission to compensate for changes in network activity. Here, we show that suppression of network activity with tetrodotoxin, which increases surface expression of AMPA receptors (AMPARs), dramatically reduces levels of the deSUMOylating (where SUMO is small ubiquitin-like modifier) enzyme SENP1, leading to a consequent increase in protein SUMOylation. Overexpression of the catalytic domain of SENP1 prevents this scaling effect, and we identify Arc as a SUMO substrate involved in the tetrodotoxin-induced increase in AMPAR surface expression. Thus, protein SUMOylation plays an important and previously unsuspected role in synaptic trafficking of AMPARs that underlies homeostatic scaling.
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http://dx.doi.org/10.1074/jbc.M112.356337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391081PMC
June 2012

SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity.

Nat Neurosci 2012 Jun;15(6):845-52

School of Physiology and Pharmacology, Medical Research Council Centre for Synaptic Plasticity, University of Bristol, Bristol, UK.

Phosphorylation or SUMOylation of the kainate receptor (KAR) subunit GluK2 have both individually been shown to regulate KAR surface expression. However, it is unknown whether phosphorylation and SUMOylation of GluK2 are important for activity-dependent KAR synaptic plasticity. We found that protein kinase C–mediated phosphorylation of GluK2 at serine 868 promotes GluK2 SUMOylation at lysine 886 and that both of these events are necessary for the internalization of GluK2-containing KARs that occurs during long-term depression of KAR-mediated synaptic transmission at rat hippocampal mossy fiber synapses. Conversely, phosphorylation of GluK2 at serine 868 in the absence of SUMOylation led to an increase in KAR surface expression by facilitating receptor recycling between endosomal compartments and the plasma membrane. Our results suggest a role for the dynamic control of synaptic SUMOylation in the regulation of KAR synaptic transmission and plasticity.
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http://dx.doi.org/10.1038/nn.3089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435142PMC
June 2012
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