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Professor Jonathan Hanley
B.A.(Cantab.), Ph.D.(U.C.Lond.)
Professor of Molecular Neuroscience
The molecular mechanisms of synaptic plasticity
Office Room G.27
Biomedical Sciences Building,
University Walk, Clifton BS8 1TD
(See a map)
jon.hanley@bristol.ac.uk
Jonathan Hanley, Reader in Molecular Neuroscience
Learning and the formation of memories involves alterations in neural circuitry, brought about by changes in synaptic strength, which are in turn underpinned by changes in the molecular machinery of synapses. We use a range of biochemical, molecular and imaging techniques, and we collaborate with electrophysiologists for analysing synaptic function. We study three aspects of synaptic plasticity: AMPA receptor trafficking, dendritic spine morphogenesis and the control of protein translation by microRNAs.
AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain, and plasticity at excitatory synapses involves alterations in the number of AMPARs localised at the synaptic plasma membrane, brought about by regulated receptor trafficking. AMPAR expression at the synaptic plasma membrane is regulated by endocytosis, exocytosis, recycling and lateral diffusion events that contribute to reductions (Long Term Depression, LTD) or increases (Long Term Potentiation, LTP) in synaptic strength.
A major focus of the lab is investigating how basic cell biological processes interact with AMPAR subunits to bring about changes in AMPAR trafficking and hence synaptic strength. In particular, we are studying a PDZ- and BAR-domain protein called PICK1, which binds AMPAR subunit GluA2, and is involved in AMPAR internalisation and LTD. We have demonstrated that PICK1 inhibits Arp2/3-mediated actin polymerisation, and that this is required for NMDA-stimulated AMPAR internalisation and LTD (Rocca et al., 2008, Nat. Cell Biol; Nakamura et al., 2011, EMBO J.; Rocca et al., 2013, Neuron). We are also studying how PICK1 interacts with core components of the endocytic machinery to regulate clathrin-coated vesicle formation (Fiuza et al., 2017, J. Cell Biol.).
As well as "normal" plasticity, we are studying AMPAR trafficking events that occur in response to acute injury, such as mechanical injury (a model for traumatic brain injury, TBI) and oxygen/glucose deprivation (OGD; a model for ischaemia). Brain ischaemia occurs when the blood supply to the brain is interrupted, for example by occlusion following a stroke, or as a result of cardiac arrest. We are studying the specific endosomal sorting steps that are involved in regulating cell-surface AMPARs in response to OGD or TBI. The majority of AMPARs contain GluA2 subunit, and consequently are Ca2+ impermeable. OGD and TBI cause trafficking events that result in the loss of surface GluA2-containing AMPARs, and therefore an increase in Ca2+ permeable AMPARs, which contribute to neuronal death. We have discovered differences in subunit-specific AMPAR trafficking events between hippocampal and cortical neurons that we propose play a role in the differential vulnerabilities to ischaemia between these neuronal types observed in vivo (Blanco-Suarez et al., 2014, J. Biol. Chem; Koszegi et al., 2017, Scientific Reports).
Dendritic spines are highly specialized subcellular compartments that contain the postsynaptic protein machinery of most excitatory synapses. They concentrate and compartmentalise biochemical signals such as Ca2+, and synaptic protein machinery such as neurotransmitter receptors, providing the synaptic specificity required for plasticity. Changes in synaptic strength correlate with corresponding changes in dendritic spine size, and possibly shape. LTD stimuli result in spine shrinkage and retraction, whereas LTP leads to the formation of new spines, or the growth of existing ones.
We are studying the molecular mechanisms that underlie changes in spine size during synaptic plasticity (Nakamura et al., 2011, EMBO J.; Rocca et al., 2013, Neuron) and also in response to OGD (Blanco Suarez et al., 2014, J.Cereb. Blood Flow Metab.).
Spines are extremely rich in dynamic actin filaments, which underlie these activity-dependent changes in spine size. LTP is thought to promote actin polymerization resulting in an increase in spine F-actin, and LTD results in reduced F-actin via actin depolymerization. The signalling pathways that lead to these changes in actin polymerization to bring about spine growth or shrinkage are affected by OGD, and we prose that manipulating these pathways holds therapeutic potential.
Long-term changes in synaptic efficacy that underlie the persistent formation of memories require changes in the synthesis of synaptic proteins by the activity-dependent regulation of local translation of mRNA in dendrites close to synapses. A role for microRNAs (miRNAs) in this process has recently become the subject of much attention. MiRNAs are small, noncoding endogenous RNA molecules that repress the translation of target mRNAs through complementary binding in the transcript 3'-untranslated region (3'-UTR). A number of miRNAs have been shown to be involved in specific forms of learning and memory, and dysfunction of miRNAs is implicated in neurological and neuropsychiatric diseases including Alzheimer's, Huntington's and Schizophrenia.
Argonaute (Ago) proteins associate with miRNAs as well as numerous additional proteins in RNA-induced silencing complexes (RISCs) to direct translational repression of target mRNAs. We are investigating how the induction of synaptic plasticity affects this process, by studying the dynamics of RISC protein-protein interactions, how they are regulated (phosphorylation, direct binding of Ca2+, etc.) and their impact on synaptic structure and function. In a current project, we have found that the interac tion between Ago2 and key RISC components including GW182 are increased by Ago2 phosphorylation in response to the induction of LTD. This mechanism leads to increased translational repression of key proteins involved in synaptic structure, and hence causes spine shrinkage (see diagram; Rajgor et al, 2018, EMBO Journal).
We have also demonstrated that PICK1 inhibits miRNA activity by binding to Ago2 on endosomal compartments in dendrites (Antoniou et al., 2014, EMBO Reports). This interaction is disrupted by Ca2+ ions, and therefore NMDAR-dependent LTD causes a dissociation of Ago2 from PICK1, increasing miRNA activity and hence translational repression (Rajgor et al., 2017, J.Biol.Chem).
We are also very interested in how these mechanisms of RISC regulation are affected by pathologies such as Alzheimer's and ischaemia.
Georgiana Stan, Omar Kassaar, Jessica Walters, Harriet Gallegos, Yasuko Nakamura
Post-doc position available!
We have recently (March 2019) secured an Alzheimer's Research UK (ARUK) grant to study the role of RISC regulation in dendritic spine loss and synaptic dysfunction in mouse models of AD.
A 3 year post-doc position is available to start late 2019.
Please contact Jon Hanley for further information.
Advanced Cell Biology
Synaptic Cell Biology
Advanced Options in Biochemistry
Functional Neuroanatomy
Techniques in Neuroscience
synaptic plasticity
dendritic spine
ischaemia.
Synaptic
School of Biochemistry staff
Biochemistry academic staff
Jon Hanley's lab webpages
Antoniou, A, Baptista, M, Carney, N & Hanley, J, 2014, 'PICK1 links Argonaute 2 to endosomes in neuronal dendrites and regulates miRNA activity.'. EMBO Reports, vol 15., pp. 548-556
Suarez, EB, Fiuza, M, Liu, X, Chakkarapani, E & Hanley, J, 2014, 'Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation.'. Journal of Cerebral Blood Flow and Metabolism, vol 34., pp. 1898-1906
Rocca, DL, Amici, M, Antoniou, A, Suarez, EB, Halemani, N, Murk, K, McGarvey, J, Jaafari, N, Mellor, JR, Collingridge, GL & Hanley, JG, 2013, 'The Small GTPase Arf1 Modulates Arp2/3-Mediated Actin Polymerization via PICK1 to Regulate Synaptic Plasticity'. Neuron, vol 79., pp. 293-307
Jaafari, N, Henley, JM & Hanley, JG, 2012, 'PICK1 Mediates Transient Synaptic Expression of GluA2-Lacking AMPA Receptors during Glycine-Induced AMPA Receptor Trafficking.'. Journal of Neuroscience, vol 32., pp. 11618-11630
Nakamura, Y, Wood, C, Patton, A, Jaafari, N, Henley, J, Mellor, J & Hanley, J, 2011, 'PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity'. EMBO Journal, vol 30 ., pp. 719 - 730
Rocca, D, Martin, S, Jenkins, E & Hanley, J, 2008, 'Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis'. Nature Cell Biology, vol 10., pp. 259 - 271
Hanley, J & Henley, J, 2005, 'PICK1 is a calcium-sensor for NMDA-induced AMPA receptor trafficking'. EMBO Journal, vol 24., pp. 3266 - 3278
Nishiguchi, A, Gilmore, C, Sood, A, Matsusaki, M, Collett, G, Tannetta, D, Sargent, IL, McGarvey, J, Halemani, ND, Hanley, J, Day, F, Grant, S, Murdoch-Davis, C, Kemp, H, Verkade, P, Aplin, JD, Akashi, M & Case, CP, 2019, 'In vitro placenta barrier model using primary human trophoblasts, underlying connective tissue and vascular endothelium'. Biomaterials, vol 192., pp. 140-148
Rajgor, D, Sanderson, T, Amici, M, Collingridge, GL & Hanley, J, 2018, 'NMDAR-dependent Argonaute 2 phosphorylation regulates miRNA activity and dendritic spine plasticity'. EMBO Journal, vol 37.
Parkinson, GT, Chamberlain, SEL, Jaafari, N, Turvey, MR, Mellor, J & Hanley, J, 2018, 'Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit'. Scientific Reports, vol 8.
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