This study will examine postnatal development of intrinsic and synaptic excitability in motoneurons from the mouse model for familial ALS, the SOD1G93A mouse. ALS is a slowly progressing disease marked by loss of motoneurons resulting in paralysis and finally death. Motoneurons that are vulnerable to ALS have low buffering capacity for intracellular calcium (Ca2+), and excitotoxicity through excessive Ca2+ entry is a possible mechanism of neurodegeneration in ALS. This study will examine changes during maturation in the two main routes excessive Ca2+ entry could occur: increased synaptic excitation and/or an increase in the intrinsic excitability of the motoneuron. Intrinsic excitability is mediated by both persistent Na+ channels (NaP) and Cav1.3 Ca2+ channels which produce the persistent inward current (PIC). Riluzole, the only FDA approved drug for ALS, works in two ways, blocking NaP, and decreasing presynaptic glutamate release. Unfortunately riluzole loses effectiveness over time, so exploration of other potential treatments for ALS is needed. Isradipine, a dihydropiradine antagonist effective in blocking Cav1.3 Ca2+ channels will be applied and motoneuron excitability will be assessed in neonatal, juvenile and adult mice. Although a major portion of the PIC consists of NaP in young rats, during maturation the contribution of Ca2+ increases to about 50%. The adult onset of ALS could be linked to this shift from a Na+ to Ca2+-mediated PIC. In Parkinson's disease, maturation of Na+-dependant pacemaker activity in juvenile substantia nigra neurons to Cav1.3- mediated activity in adults causes degeneration, and if Na+-dependent activity is brought back in adults with prolonged exposure to isradipine, these neurons were less susceptible to the disease. A similar Ca++ dependent susceptibility could develop in aging motoneurons of SOD1G93A mice, and isradipine could be an effective treatment. Therefore I propose to study intrinsic and synaptic excitability, including somal and dendritic Ca2+ levels in normal and SOD1G93A mice and the effects of short- and long-term isradipine exposure on motoneuron hyperexcitability in SOD1G93A mice from neonatal through adult ages. I will record from lumbar and sacral motoneurons using whole cell patch clamp and sharp electrode intracellular recording, and using multiphoton imaging and Ca2+ sensitive dye, examine dendritic Ca2+ influx at all timepoints. This study will assess the potential of a new treatment for ALS, isradipine, a drug currently FDA approved for management of hypertension. In addition, this work may reveal more accurate methods of early ALS diagnosis, through evaluation of the reflex responses from the leg muscles.
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