Reduced Motoneuron Excitability in Sepsis

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DESCRIPTION (provided by applicant): Weakness is a major complication of critical illness that complicates recovery both during the first few weeks following illness as well as the quality of life 1 to 2 years after the illness. During the acute recovery period, weakness often prevents patient weaning from the ventilator, prolonging intensive care unit stays, and leading to greatly increased cost, complication rates and mortality. In a recently published paper we found, in both patients and rats, that difficulty in recruitment of motoneurons to fire is an important contributo to weakness triggered by critical illness. Preliminary data presented in this grant suggests difficulty recruiting motoneurons to fire may persist after recovery from critical illness and thus may contribute to long term weakness. Reduced motoneuron excitability as a mechanism of weakness has never been proposed and thus represents a novel area of research into weakness triggered by critical illness. In vivo intracellular recording from motoneurons in adult rats will be used in combination with modeling of motoneuron excitability to identify potential mechanisms underlying the reduction of excitability. Potential mechanisms will further be explored using dynamic clamp of motoneurons in vivo to correct the defect(s) in ion channels that underlie the reduction in excitability. Preliminary data suggests we have identified a class o drugs that can correct the defect in excitability. It is our hope that identification of drugs that improve motoneuron excitability will rapidly translate to new therapy that improves the rate of rehabilitation and the quality of life for patients after hospital discharge.