MRC Centre for Synaptic Plasticity
School of Medical Sciences University of Bristol
Anatomy Department
University Walk
BS8 1TD - Bristol
United Kingdom

+44 117 331 1944
+44 (0)117 331-2288
jack.mellor@bristol.ac.uk

Job opportunities

Our ability to learn and remember information about our environment is thought to be underpinned by the process of synaptic plasticity. This means that during learning episodes, synapses are stimulated by specific patterns of activity that lead to the induction of synaptic plasticity. Subsequently, plasticity is expressed either by the insertion or removal of postsynaptic neurotransmitter receptors or by changes in the amount of neurotransmitter released from the presynaptic terminal.

Research in our laboratory is focused on what regulates the induction of synaptic plasticity and also the mechanisms underlying its expression. Currently we are studying, 1) The patterns of activity that induce synaptic plasticity, 2) The regulation of neuronal excitability and the effect this has on the induction of synaptic plasticity, and 3) The mechanisms underlying postsynaptic glutamate receptor trafficking. This work is mainly performed using electrophysiological recordings from neurones in brain slices.

Current projects:

The neuronal activity patterns required for synaptic plasticity induction.
The hippocampus is believed to encode episodic memories (or memory for events) by the process of synaptic plasticity. However, the precise events that occur during learning to induce synaptic plasticity are currently unknown. Finding out what these are would represent a major advance in our understanding of how learning and memory are encoded. We investigate this problem by analysing the patterns of neuronal activity that induce synaptic plasticity and how these patterns relate to those that occur during learning episodes. In collaboration with Prof Robert Muller and Dr Matt Jones, we make use of hippocampal place cell recordings that occur in the hippocampus during spatial learning tasks. We can then replay these activity patterns into neurones within a brain slice to assess their ability to induce synaptic plasticity (Isaac et al., 2009). Using artificial neuronal activity patterns we can also determine the critical activity patterns required to induce synaptic plasticity (Buchanan and Mellor, 2007).

Regulation of neuronal excitability and its effect on synaptic plasticity.
Changes in neuronal excitability brought about by neuromodulators or long-term changes in ion channel properties alter the manner in which neurones process incoming information. We are interested in understanding how this occurs and how it affects the induction of synaptic plasticity. Previously, we found a role for ion channel modulation in hippocampal granule cell excitability (Mistry and Mellor, 2007) and we are currently investigating how this affects synaptic plasticity. Recently, we have also found a critical role for the neuromodulator acetylcholine in the induction of synaptic plasticity by naturally occurring activity patterns (Isaac et al., 2009) and we are currently investigating the mechanisms underlying the action of acetylcholine.

Glutamate receptor trafficking.

In collaboration with Dr Jonathan Hanley we investigate the role of PICK-1 in AMPA receptor trafficking (Dixon et al., 2009) and with Prof Jeremy Henley we investigate the role of SUMOylation in kainate receptor trafficking (Martin et al, 2007). We use genetic modifications of specific neurones within hippocampal slices to assess the role of these proteins in synaptic glutamate receptor expression.

Konopacki, FA, Jaafari, N, Rocca, DL, Wilkinson, KA, Chamberlain, S, Rubin, P, Kantamneni, S, Mellor, JR & Henley, JM (2011). Agonist-induced PKC phosphorylation regulates GluK2 SUMOylation and kainate receptor endocytosis. PNAS (in press).

Sadowski, JHLP, Jones, MW & Mellor, JR (2011). Ripples make waves: binding structured activity and plasticity in hippocampal networks. Neural Plasticity 2011, 960389.

Dennis, SH, Jaafari, N, Cimarosti, H, Hanley, JG, Henley, JM & Mellor, JR (2011). Oxygen/glucose Deprivation Induces a Reduction in Synaptic AMPA Receptors on Hippocampal CA3 Neurons Mediated by mGluR1 and A3 Receptors. J Neurosci 31, 11941-52.

Nakamura, Y, Wood, CL, Patton, AP, Jaafari, N, Henley, JM, Mellor, JR & Hanley, JG (2011) PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity. EMBO 30, 719-730.

Buchanan, KA, Petrovic, MM, Chamberlain, SEL, Marrion, NV & Mellor, JR (2010). Facilitation of Long-Term Potentiation by Muscarinic M1 Receptors is mediated by inhibition of SK channels. Neuron 68, 948-963.

Rackham, O.J.L., Tsaneva-Atanasova, K., Ganesh, A., and Mellor, J.R. (2010). A Ca2+-based Computational Model for NMDA Receptor-Dependent Synaptic Plasticity at Individual Postsynaptic Spines in the Hippocampus. Frontiers in Synaptic Neuroscience 2, 31.

Buchanan, K.A., and Mellor, J.R. (2010). The activity requirements for spike timing-dependent plasticity in the hippocampus. Frontiers in Synaptic Neuroscience 2, 11.

Mistry, R., Dennis, S., Frerking, M. & Mellor, J.R. (2010). Dentate Gyrus Granule Cell Firing Patterns Can Induce Mossy Fiber Long-Term Potentiation In Vitro. Hippocampus 21, 1157–68.

Isaac, J.T., Bucahanan, K.A., Muller, R.U. and Mellor, J.R. (2009). Hippocampal place cell firing patterns can induce long-term synaptic plasticity in vitro. Journal of Neuroscience 29, 6840-6850.

Dixon, R.M., Mellor, J.R.*, and Hanley, J.G. (2009). PICK1-mediated Glutamate Receptor Subunit 2 (GluR2) Trafficking Contributes to Cell Death in Oxygen/Glucose-deprived Hippocampal Neurons. Journal of Biological Chemistry 284, 14230-14235.

Mistry, R. & Mellor, J.R. (2008). Bidirectional activity-dependent plasticity of membrane potential and the influence on spiking in rat hippocampal dentate granule cells. Neuropharmacology 54, 290-299.

Buchanan, K.A. & Mellor, J.R. (2007). The development of synaptic plasticity induction rules and the requirement for postsynaptic spikes in rat hippocampal CA1 pyramidal neurones. Journal of Physiology 585, 429-445.

Martin, S., Nishimune, A., Mellor, J.R.* & Henley, J.M. (2007). SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447, 321-325.

Mellor, J. (2006). Synaptic plasticity of kainate receptors. Bioscience Transactions 34, 949-951.

Bannister, N., Benke, T.A., Mellor, J., Scott, H., Gurdal, E., Crabtree, J.W. & Isaac, J.T.R. (2005). Developmental Changes in AMPA and Kainate Receptor-Mediated Quantal Transmission at Thalamocortical Synapses in the Barrel Cortex. Journal of Neuroscience 25, 5259-5271.

Isaac, J.T.R., Mellor, J., Hurtado, D. & Roche, K.W. (2004). Kainate Receptor Trafficking: Physiological Roles and Molecular Mechanisms. Pharmacology and Therapeutics 104, 163-172.

Schmitz, D., Mellor, J.*, Breustedt, J. & Nicoll, R.A. (2003). Presynaptic kainate receptors impart an associative property to hippocampal mossy fiber long-term potentiation. Nature Neuroscience 6, 1058-1063.

Mellor, J., Nicoll, R.A. & Schmitz, D. (2002). Mediation of Hippocampal Mossy Fiber Long-Term Potentiation by Presynaptic I_h Channels. Science 296, 143-147.

Misawa, H., Kawasaki, Y., Mellor, J., Sweeney, N., Jo, K., Nicoll, R.A. & Bredt, D.S. (2001).  Contrasting localizations of MALS/LIN-7 PDZ proteins in brain and molecular compensation in knockout mice. Journal of Biological Chemistry 276(12), 9264-72.

Schmitz, D., Mellor, J. & Nicoll, R.A. (2001). Presynaptic kainate receptors mediate frequency facilitation at hippocampal mossy fiber synapses. Science 291, 1972-1976.

Schmitz, D., Mellor, J., Frerking, M. & Nicoll, R.A. (2001). Presynaptic kainate receptors at hippocampal mossy fiber synapses. PNAS 98, 11003-11008.

Mellor, J. & Nicoll, R.A. (2001). Hippocampal mossy fiber LTP is independent of postsynaptic calcium. Nature Neuroscience 4, 125-126.

Nicoll, R.A., Mellor, J., Frerking, M. & Schmitz, D. (2000). Kainate receptors and synaptic plasticity. Nature 406, 957.

Vogt, K.E., Mellor, J.R.*, Tong, G. & Nicoll, R.A. (2000). The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron 26(1), 187-196.

Mellor, J.R. & Randall, A.D. (2001). Synaptically released neurotransmitter fails to desensitise postsynaptic GABA_A receptors. Journal of Neurophysiology 85, 1847-1857.

Leao, R.M., Mellor, J.R. & Randall, A.D. (2000). Tonic benzodiazepine-sensitive GABAergic inhibition in cultured rodent cerebellar granule cells. Neuropharmacology 39(6), 990-1003.

Mellor, J.R., Gunthorpe, M.J. & A.D. Randall (2000). The taurine uptake inhibitor guanidinoethyl sulphonate is an agonist at GABA_A receptors in cultured cerebellar granule cells. Neuroscience Letters 286, 25-28.

Mellor, J.R., Wisden, W. & Randall, A.D. (2000). Somato-synaptic variation of GABA_A receptors in cultured murine cerebellar granule cells: investigation of the role of the a6 subunit. Neuropharmacology 39, 1495-1513.

Williamson, A.V., Mellor, J.R., Grant, A. & Randall, A.D. (1998). Unusual low-affinity benzodiazepine insensitive GABA_A receptors in cultured rat O-2A progenitor cells. Neuropharmacology 37, 859-873.

Mellor, J.R., Merlo, D., Jones, A., Wisden, W. & Randall, A.D. (1998). Mouse cerebellar granule cell differentiation: Electrical activity regulates the GABA_A receptor a6 subunit gene. Journal of Neuroscience 18(8), 2822-2833.

Mellor, J.R. & Randall, A.D. (1998). Voltage-dependent deactivation and desensitization of GABA responses in cultured murine cerebellar granule cells. Journal of Physiology 506, 377-390.

Mellor, J.R. & Randall, A.D. (1997). Frequency-dependent actions of benzodiazepines on GABA_A receptors in cultured murine cerebellar granule cells. Journal of Physiology 503, 353-369.

Jones, A., Korpi, E.R., McKernan, R.M., Pelz, R., Nusser, Z., Makela, R., Mellor, J.R., Pollard, S., Bahn, S., Stephenson, F.A., Randall, A.D., Sieghart, W., Somogyi, P., Smith, A.J.H. & Wisden, W. (1997). Ligand-gated ion channel subunit partnerships: GABA_A receptor a6 subunit gene inactivation inhibits d subunit expression. Journal of Neuroscience 17(4), 1350-1362.

Electrophysiology in acute and cultured brain slices.