Pattinson, Damian Thomas; (2004) The role of calcium/calmodulin-dependent kinase IIα on the development and plasticity of sensory pathways. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The dorsal horn of the spinal cord undergoes alterations during early postnatal life. For example, the primary afferent terminations from low-threshold Aβ fibres reorganise, and the interneurones increase their axodendritic elaborations. Many of these changes require activation of the NMDA receptor. The aim of this thesis was to examine the role of a major downstream signalling protein- calcium/calmodulin-dependent kinase II- in the activity-dependent development of the dorsal horn. After confirming the presence of the kinase in the spinal cord from birth, and elucidating its localisation within this region, I obtained a transgenic mouse in which a point mutation of the T286A site (T286A) prevents the kinase from entering its autophosphorylated form, and thus from remaining active after dissipation of the calcium stimulus. Using Dil labelling of Aβ fibres, it was shown the postnatal reorganisation that normally occurs during development, but is prevented by chronic NMDA receptor blockade, was not affected by the mutation, suggesting that CaMKII autophosphorylation is not required for normal A fibre development. Electrophysiological analysis of the dorsal horn using in vitro whole-cell patch clamp and in vivo extracellular recordings revealed decreases in polysynaptic Aβ input to the superficial dorsal horn, combined with reduced C fibre input and increased neuronal receptive field sizes in the mutant compared with wild-type littermates. This suggests a role for CaMKII in the normal postnatal development of the dorsal horn intemeuronal connectivity. Finally, the pain-processing ability of the adult mutant mouse was examined using behavioural and electrophysiological techniques. It was found that, while the baseline sensory processing was unaffected in the mutant, there was a decrease in pain behaviour in response to intraplantar injection of formalin, accompanied by an increase in pain behaviour in response to nerve injury. These findings highlight the different mechanisms that control pain processing in the spinal cord, and suggest different roles for CaMKII in each of these mechanisms.

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