Professor Nick Hartell

Tel:  +44 (0)116 252 3301       Email:  nh88@le.ac.uk

Publications

Hartell NA (2006). Simple windows-based software for the control of laser scanning confocal microscopes. J Neurosci Methods.

Sims RE and Hartell NA (2006). Differential susceptibility to synaptic plasticity reveals a functional specialization of ascending axon and parallel fiber synapses to cerebellar Purkinje cells. J Neurosci 26, 5153-5159.

Sims RE and Hartell NA (2005). Differences in Transmission Properties and Susceptibility to Long-Term Depression Reveal Functional Specialization of Ascending Axon and Parallel Fiber Synapses to Purkinje Cells. J Neurosci 25, 3246-3257.

Sekaran S, Cunningham J, Neal MJ, Hartell NA and Djamgoz MB (2005). Nitric oxide release is induced by dopamine during illumination of the carp retina: serial neurochemical control of light adaptation. Eur J Neurosci 21, 2199-2208.

Hartell NA, Archer HE and Bailey CJ (2005). Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochemical Pharmacology 69, 781-790.

Other key publications

Hartell NA (2002). Parallel fiber plasticity. The Cerebellum 1, 3-18.

Hartell NA, Furuya S, Jacoby S and Okada D (2001). Intercellular action of nitric oxide increases cGMP in cerebellar Purkinje cells. NeuroReport 12, 25-28.

Jacoby S, Sims RE and Hartell NA (2001). Nitric Oxide is required for the induction and heterosynaptic spread of cerebellar LTP. J Physiol (Lond ) 535, 825-839.

Reynolds T and Hartell NA (2001). Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD. NeuroReport 12, 133-136.

Hartell NA (2001). Receptors, second messengers and protein kinases required for heterosynaptic cerebellar long-term depression. Neuropharmacol 40, 148-161.

Hartell NA (2000). Dynamic changes in nitric oxide and cyclic-GMP production in response to cerebellar molecular layer stimulation. Eur J Neurosci 12, 19.

Reynolds T and Hartell NA (2000). An evaluation of the synapse-specificity of long-term depression induced in rat cerebellar slices. J Physiol (Lond ) 527, 563-577.

Hartell NA (1996). Strong activation of parallel fibers produces localized calcium transients and a form of LTD that spreads to distant synapses. Neuron 16, 601-610.

Hartell NA (1996). Inhibition of cGMP breakdown promotes the induction of cerebellar long-term depression. J Neurosci 16, 2881-2890.

Research

Interests and techniques

A central theme of the research carried out in this laboratory is the cellular mechanisms of memory storage. Please visit our Alternative Web Pages for more detailed information.

Nick Hartell Research Page Image 1

Memory is thought to be encoded as long lasting changes in the strength of signalling between synapses formed by excitable cells in the brain. By gaining a better understanding of the mechanisms responsible for memory acquisition, we aim to improve our ability to enhance the brains capacity to learn and develop strategies for repair following injury or neurodegenerative diseases that affect memory, such as Alzheimer’s disease.

One of the models of synaptic plasticity that we study is the long-term depression of transmission at the synapse formed between cerebellar granule cells and Purkinje cells. So called LTD may provide the mechanism for learning in the motor system, allowing acquisition of skilled movements during development and practice. Over the last few years, we have examined the contributions of numerous receptors and second messengers to LTD and other forms of plasticity at this synapse, including calcium, nitric oxide, cyclic AMP, cyclic GMP and arachidonic acid.

We have recently discovered that synapses formed by ascending and parallel fibre segments of the granule cell axon to Purkinje cells have different transmission characteristics (Sims and Hartell 2005). This allows each segment of the axon to convey different types of information to Purkinje cells depending on the position of the synapse, unveiling a hitherto unrecognised level of complexity to parallel fibre-Purkinje cell signalling. By transmitting different signals down the same pathway, this is analogous to the transmission of telephone and broad band signals down the same telephone connection. We are currently devising methods to visualise transmission at these synapses to further establish what impact these differences have on cerebellar processing.

Nick Hartell Research Page Image 2

Much of our work involves simultaneous slice patch recording from one or more cells and fluorescent imaging with CCD or confocal based microscopy. In collaboration with Professor Anne Stephenson at the School of Pharmacy, London, we are now bringing molecular biological techniques to bear on our research efforts and using these to develop methods that allow us to visualise changes in synaptic signalling in real time.

Current projects

Defining a 3-dimensional network of plasticity in the cerebellar cortex (BBSRC)

Several forms of plasticity at granule cell-Purkinje cell synapses involve second messengers that are diffusible and so capable of trans-cellular movement. We have previously shown that forms of LTD and LTP in the cerebellum do not remain synapse specific but plasticity spreads to synapses formed by the same cell over distances of several tens of microns. In view of the anatomical structure of parallel fibres, which form numerous synapses with Purkinje cells across several millimetres of cortex, and given the involvement of diffusible second messengers such as nitric oxide in both LTP and LTD, we are characterising the extent to which plasticity spreads between cells connected by common parallel fibre inputs.

Visualising Synaptic Plasticity (BBSRC)

The insertion and removal of receptors from the post-synaptic membrane provide a mechanism for long-term changes in transmission strength at central synapses. We are currently testing the hypothesis that glutamate receptor trafficking underpins forms of plasticity at granule cell-Purkinje cell synapses.

By tagging novel, pH sensitive fluorescent protein constructs to subunits of the AMPA subtype of glutamate receptor, we can distinguish surface expressed receptors from those inside the cell and detect receptor trafficking to and from the plasma membrane. The images below show surface receptors selectively highlighted in red and their intracellular movement under conditions known to trigger LTD.

Nick Hartell Research Page Image 3

Visualising vesicle movement and transmitter release (BBSRC)

Transmitters are released from vesicles in presynaptic terminals. Inside vesicles, the pH is around 6. During release, the inside of the vesicle comes into brief contact with the extracellular environment which is at pH 7.4. By tagging parts of vesicular proteins exposed to the lumen of vesicles with pH sensitive fluorescent proteins, it is possible to visualise the process of release. Current methods utilise a sensor called synaptopHluorin, which is a construct of the pH sensor super-ecliptic pHluorin and the vesicular protein synaptobrevin (aka VAMP).

This has proved very useful but synaptopHluorin is quenched at the low pH found in non-releasing vesicles making them “invisible”. It is also expressed in non -vesicular membranes causing a significant reduction in overall sensitivity. We are now creating probes that combine a novel, fluorescent protein based pH sensor with various vesicular proteins with the aim of developing a tool that can distinguish releasing vesicles from those present in the presynaptic terminal that are not actively involved in release.

Development of a high speed, optically sectioning, random access microscope (BBSRC)

We have recently developed software for the control of confocal microscopes with the intentions of simplifying their use in conjunction with electrophysiological recordings. We are currently embarking on a project funded by the BBSRC to develop a new type of confocal microscope that allows high speed recording from individual cells or from selected points of interest from single cells.

Techniques

  • Fluorescent measurements of receptors and second messengers
  • Laser scanning confocal microscopy in combination with electrophysiological recordings
  • Patch clamp recording from brain slices
  • Optical imaging development
  • Molecular biology
  • The use of PH sensors to monitor transmitter release and receptor trafficking in models of leaning

Research group and funding

Present group members

Albert Okorocha

Jo Shaw

Vanessa Keasberry

Hana Smeda

Current funding

BBSRC Visualising neuronal activity and plasticity

BBSRC Development of a high speed, optically sectioning random access microscope

BBSRC Use of a ratiometric pH sensor for the live imaging of a transmitter release in the CNS Royal Society

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Contact

Department of Neuroscience, Psychology and Behaviour
University of Leicester
University Road
Leicester
LE1 7RH

T: +44 (0)116 252 2922
E: npbenquiries@le.ac.uk

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