Award details

Distribution and modulation of dynamic sodium pumps in a spinal motor network

Reference	BB/T015705/1
Principal Investigator / Supervisor	Professor Keith Sillar
Co-Investigators / Co-Supervisors	Dr Lamia Hachoumi
Institution	University of St Andrews
Department	Psychology
Funding type	Research
Value (£)	583,802
Status	Current
Type	Research Grant
Start date	05/10/2020
End date	04/10/2023
Duration	36 months

Abstract

Na+ pumps are expressed at high densities in virtually all cells and tissues across all stages of development. They shuttle Na+ ions out and K+ ion into cells in a 3:2 ratio to establish an ionic gradient that regulates critical cellular processes, expending ~50% of total cellular energy to accomplish this. Malfunctioning Na+ pumps contribute to many conditions, including cardiovascular disease, diabetes and neurodegenerative diseases. In neurons, Na+ pumps continuously regulate the resting membrane potential (RMP), enabling action potentials to occur. However, some Na+ pumps respond "dynamically" to intense neuronal firing, forming a recruitable reserve pool that adds to the RMP so that when activity ceases the RMP is even more negative, counteracting over-excitation homeostatically. We termed this event the ultra-slow afterhyperpolarisation (usAHP), which has now been observed in several neuronal circuits. We are at the dawn of understanding dynamic Na+ pump physiology in neuronal circuits. Only in locomotor circuits have their roles been studied in any detail. My lab was the first to describe them in the Xenopus tadpole spinal cord where the usAHP mediates a form of short-term motor memory, linking future to past activity. Neuromodulators can modify dynamic Na+ pump function, but little is known about the impact of this modulation on neuronal network function and behaviour. Our preliminary data reveals the usAHP is profoundly modulated by amines and nitric oxide. We will test our hypothesis that auxiliary "FXYD" pump subunits expressed in Xenopus and humans alike underlie this modulation. This timely project will explore and model dynamic Na+ pump distribution among identified neurons at the molecular, cellular and network levels linking their modulation to motor memory and locomotor behaviours. This is not currently feasible in any other system so our research will be novel and impactful, with profound implications for future neuroscience research.

Summary

One of the most prevalent and important proteins in the human body is the sodium pump. It is present in high numbers in every cell across all tissues of the body, even in the fertilized egg from which we develop. Moreover, the same protein is also found in every species of the animal kingdom where it has the same structure and performs the same function as it does in humans. What do sodium pumps do that is so important, and has been remained almost unchanged after a billion years of evolution? Sodium pumps control the amounts of two key ions in the cells of the body, sodium and potassium. The pumping role involves moving 3 sodium ions out for 2 potassium ions in to cells with each pump cycle. This action is repeated up to 200 times per second, and there are millions of pumps in each cell! The end result is that the outside of cells have high sodium and the inside high potassium concentrations, a situation crucial for the healthy actions of the heart and blood vessels, the kidneys and the nerve cells of the brain and spinal cord. Each pump cycle consumes energy and because of the prevalence of sodium pumps and the fact that they must always be active, they account for a staggering 50% of our energy use. A measure of how much we rely on sodium pumps is what happens when they malfunction or their expression is altered, for example, in heart disease, diabetes and motor neuron disease. We are still trying to understand the role of sodium pumps in these diseases and find new drugs to help alleviate the symptoms, but this goal is severely hindered by the fact that we still do not understand how they work. This is especially true in the brain and spinal cord and it is here that our project will seek to make new scientific discoveries on how sodium pumps actually work in nerve cells and control our behaviours. The human brain is probably the most complex structure in the Universe so we will use a much simpler system to explore the role of sodium pumps, one in which thereis a very real chance of answering the important, unresolved questions about these pumps. The small Xenopus frog tadpole has the most completely understood spinal cord network of all vertebrates. All of the nerve cells have been described in detail and also how they connect together to control the animals swimming movements. Seven years ago, we discovered a particular type of sodium pump found only in some neurons of the spinal cord. It is normally silent and only begins pumping ions when the tadpole swims fast. When the activity stops, the increased pumping reduces the ability of the spinal cord to produce another bout of swimming so the pumps produce a memory trace of past activity. Our experiments aim to find out what makes these pumps different to the others by testing our hypothesis that they have a specialised "alpha 3" version of the protein subunit that can "sense" when the tadpole is swimming. We also recently discovered that the pump action can be modulated by certain hormones and neurotransmitters, such as serotonin and dopamine, and this affects the memory system of the spinal swimming circuit. We want to learn more about this because it is relevant to the way that all animals control their movements during locomotion. Although simpler, the tadpole spinal cord is still extremely complex, but the circuit controlling its movements is similar in organisation to that found in mammals. To help validate our ideas and come up with new ones we will also simulate the circuit in a computer and add in the special alpha 3 sodium pumps. This work is timely and important because the gene that makes alpha 3 pumps (called ATP1A3) is present in both humans and young tadpoles. Unfortunately, mutations in alpha 3 pumps are linked with motor neuron disease and a form of Parkinson's syndrome. Our project has the potential to break important new ground in sodium pump research at a time when the field is being revolutionised and fuel future drug developments.

Impact Summary

Public Engagement: As detailed in Pathways to Impact (attached), we are committed to public engagement activities that increase awareness and understanding of science. The PI will continue to participate regularly in science fairs and PE events. In 2015, he created TADSCO as a vehicle to engage with local Scottish primary schools (e.g. Thornton Primary and Kinloch Rannoch Primary. Excess to requirement tadpoles generated from the Xenopus breeding colony in St Andrews are provided to schools to allow children to learn basic principles of animal welfare and husbandry, motor behaviour and development, including metamorphosis. We will continue to engage with these schools and develop new creative ways to interact by generating information packs, teaching resources and impact assessment sheets. Researchers on the grant will participate and undergraduate student interns and final year PE projects will deliver the impact. We will continue with this target audience and engage with 4 schools per year of the grant's duration. TADSCO also provides resources and support for advanced high school biology projects at Madras College, a state school in St Andrews. Social media: As a fast and efficient way to communicate science to a wider audience, we will post new research findings on ResearchGate and Twitter, with assistance from the publishers if applicable to coincide with new publications. Student interns will be engaged to aid in the design and making of Youtube videos to explain how the spinal cord generates rhythmic motor behaviour in Xenopus tadpoles and the remarkable transformation that occurs during metamorphosis, which will be accessible via our website. Software: Bill Heitler's NeuroSim programme used to model the swim circuit, was designed for advance level teaching as well as research use. We will extend use of the programme for public engagement via https://www.st-andrews.ac.uk/~wjh/ and interact with local schools teachers (see above) to introduce students to anunderstanding of basic neurobiology, from electrical excitability and action potentials to how neurons communicate with each other in circuits via synapses to generate rhythmic motor behaviour. Training highly skilled researchers: The Researcher Co-I is highly skilled in the demanding in-situ electrophysiological techniques that are critical to maintaining the UK skills base in this core area of neuroscience and this expertise will be communicated to research students in St Andrews. In addition, her skills in other areas such as computer modelling and biochemistry will be developed through collaborations on this grant. She will gain invaluable career skills in project management, including financial management. The Researcher Co-I will be supported by specialist staff employed by our university for professional development training (CAPOD) and will increase her skills through participation in activities and attendance at the BBSRC-run media training workshop (2020) or similar programs ran by our University media offices. Knowledge exchange: Simpler animal models in basic neuroscientific research are fundamentally important to the Open Science Knowledge Base. We will ensure that newsworthy research outcomes are disseminated to the general public and will engage with the University Press office at every opportunity. We will also communicate both journal publications and noteworthy advances to BBSRC Media Office. Although our project addresses basic research questions the outcomes have the potential to be exploited, for example in terms of potential novel drug targets. We will liaise with the Knowledge Transfer arm of the University Research and Innovation Service should IP opportunities arise.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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