Regulation of Arp2/3-mediated actin polymerisation by PICK1 in neuronal function

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Nerve cells (neurons) in the brain communicate with one another at connections called synapses. A chemical (neurotransmitter) is released from a neuron and travels across the synapse to activate receptors in the adjacent neuron. Synapses can change their strength (known as 'synaptic plasticity') by altering the number of receptors found on the surface of the neuron in the synapse. This process is thought to underlie learning and memory, because the memory is likely to be stored in a circuit of interconnected neurons. An important mechanism for moving receptors around neurons involves a protein called actin, which forms filaments that shrink and grow to physically manoeuvre parts of the cell or its constituents. We have found that a protein (called PICK1) is involved in controlling the formation of these actin filaments, and in this way controls the movement of neurotransmitter receptors to or from the synapse. Individual neurons are constituents of neuronal circuits that control complex behaviour or memory systems, and these neurons receive various inputs that trigger biochemical reactions inside them. These biochemical reactions can influence countless different processes in cells, and we propose that PICK1's regulation of actin could be controlled in this way. Therefore, in the proposed research, we aim to investigate how PICK1 is 'switched on' or 'switched off' with respect to its control of actin filaments. We are going to investigate three types of biochemical reaction in this work, all of which are specific varieties of well-known cellular mechanisms. We will initially carry out experiments on protein molecules in test-tubes to study the biochemical processes, and then do experiments in living neurons cultured in vitro to investigate how manipulating these biochemical reactions affects synaptic plasticity. We will use two approaches to study synaptic plasticity in neurons. First, we will visualise the movement of neurotransmitter receptors using microscopy, and second, we will analyse the activity of neurons by recording their electrical activity. This work is important because it will lead to a wealth of new information about synaptic plasticity, and hence learning and memory mechanisms. The movement of neurotransmitter receptors to and from the synapse is thought to underlie the altered neuronal activity in several brain diseases, such as stroke, Alzheimer's, and also in drug addiction. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases, and may contribute to developing therapies. In addition, the control of actin is absolutely essential to numerous processes in all of the cells in our bodies, not just neurons. Therefore, this work will provide important information that will enhance the study of many other cellular processes and disease mechanisms.