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. 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.

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.

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.

Group members

Georgiana Stan, Aidan Kenny, Jessica Walters, Fathima Murshida, Sofia Raak, Kate Pring