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Neuronal circuitry and plasticity of the spinal cord using in-vivo electrophysiology in transgenic mice

Final Report Summary - MICE SPINAL CORD CM (Neuronal circuitry and plasticity of the spinal cord using in-vivo electrophysiology in transgenic mice)

Project context and objectives

The project had the following aims:

- to develop the techniques for intracellular recordings of spinal neurones previously used in larger animals (e.g. a cat) for the adult mouse in vivo;
- to describe the intrinsic properties of mouse motoneurones and to compare those properties with those described in the cat and the rat;
- to investigate differences in various transgenic strains.

Work performed

Larger animals have traditionally been used for in vivo intracellular recording in the adult spinal cord due to the stability needed for intracellular penetrations with fine electrodes and the robustness of the preparation to withstand the surgical procedures. To be able to take advantage of the developments in transgenic mice so as to understand both normal spinal function and its dysfunction in disease, it is necessary to adapt previous techniques used in the larger animals and transfer them to the mouse.

Main results

We successfully developed a laboratory capable of intracellular recording from identified spinal motoneurones in the adult mouse in vivo. Using these adapted techniques, we identified key intrinsic properties of the motoneurones. We then extended the model to include a decerebrate preparation and compared these results with those obtained using different anaesthesias. Using the decerebrate in vivo model we also demonstrated that is it possible to pharmacologically activate spinal 'central pattern generators', such as locomotion, simultaneously with intracellular recording. By applying the model to transgenic models of human disorders, we explored the hypothesis of an increased level of excitability in a transgenic mouse model of the human motoneurone disease, Amyotrophic Lateral Sclerosis (ALS), demonstrating that the increased excitability seen in the neonatal in vitro preparations extends into adulthood. These results have been disseminated in the form of published manuscripts in peer reviewed journals (three so far) and in abstract form at various international meetings. The work has also been covered by Insight Publishers / Projects 27, pp 54-56 in an article named 'Mice models build a bridge' (see for more detail).

This grant has allowed us to establish a laboratory here in Europe, which is currently one of a handful worldwide that are capable of conducting such experiments in the adult mouse spinal cord in vivo. This has culminated in a number of potentially high profile international collaborations. In the coming years we will use the in-vivo model to study transgenic mice with specific manipulations that affect the development of spinal neuronal circuitry and those that have genetic mutations similar to those underlying neurological disorders in humans.

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