Jonathan Hanley, Professor of Molecular Neuroscience

jon.hanley@bristol.ac.uk

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 and with behavioural neuroscientists to investigate memory processes. We study three aspects of synaptic plasticity: AMPA receptor trafficking, dendritic spine morphogenesis and the control of protein translation by microRNAs. In recent years, the main focus has been on miRNA systems in the control of gene expression that in turn regulates AMPARs or spines.

AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain.  Plasticity at excitatory synapses involves alterations in the number of AMPARs localised at the synaptic plasma membrane, brought about by regulated endocytosis, exocytosis, recycling and lateral diffusion events that contribute to reductions (Long Term Depression, LTD) or increases (Long Term Potentiation, LTP) in synaptic strength. We are interested in how basic cell biological processes interact with AMPARs to bring about changes in trafficking. In particular, a PDZ- and BAR-domain protein called PICK1 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 have also shown that PICK1 interacts with core components of the endocytic machinery to regulate clathrin-coated vesicle formation (Fiuza et al., 2017, J. Cell Biol.). 

Dendritic spines are 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 morphology. LTD stimuli result in spine shrinkage and retraction, whereas LTP leads to the formation of new spines, or the growth of existing ones.

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 via microRNAs (miRNAs). 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.

The main focus of the lab currently is investigating the role of Ago2 phosphorylation and the consequent gene silencing events in learning and memory in vivo.

Group members

Grace Ryall, Suifan Yang, Dhruv Singh Chauhan