| Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that predominantly affects motoneurons. One pathological feature of ALS is motoneuron hyperexcitability, and in a mouse model of ALS, there is a presymptomatic upregulation of a depolarizing persistent inward current (PIC). The PIC helps to set the intrinsic excitability of motoneurons. Riluzole, the only FDA approved drug for ALS, decreases motoneuron excitability by inhibiting the sodium component of the PIC at low therapeutic concentrations. Conversely, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are sometimes prescribed to treat depression in ALS patients but facilitate the PIC by increasing serotonin levels. Chapter 1 provides an introduction to these topics.;The goal of this research was to determine how the long term use of these drugs is related to ALS disease progression. It is already known that riluzole increases survival by 2-3 months in ALS patients but does not confer lasting protection. Chapter 2 therefore asks if prolonged riluzole exposure results in a compensatory upregulation of the PIC or if motoneurons become desensitized to riluzole. Either outcome could help to explain riluzole's transient protection in ALS. Instead, we show that the PIC is not upregulated and that riluzole remains effective at decreasing the PIC after 4-9 days of exposure on cultured primary spinal motoneurons.;Unlike riluzole, the effects of SSRIs on ALS disease progression have not been systematically studied. Chapter 3 therefore follows disease progression during three different treatment paradigms. In the first study, fluoxetine was administered neonatally for 7 days. This time period corresponds with a known increase in the PIC. In the second and third studies, fluoxetine was chronically administered from either postnatal day 30 or 70 until end stage. These studies were used to determine if presymptomatic fluoxetine treatment or treatment started near the onset of clinical symptoms would affect disease progression. Short term neonatal fluoxetine treatment was detrimental to motor performance, but adult chronic treatment had no effect. The results suggest that the neonatal upregulation of the PIC is an important factor in later disease progression and that drug intervention at this time can change the time course of the disease. |
