Fellowship in support of Quinlan, Katharina A: Spinal inhibition in ALS

It has been recently proposed that individual neurons have an activity set point, and adjustments in intrinsic properties and synaptic strengths are made to maintain this point, allowing neural networks to continue functioning despite perturbations [3]. Evidence for this is abundant in the spinal locomotor network. For example, during postnatal development motoneuron (MN) activity can be chronically increased or decreased with tetanus toxin or botulinum toxin, respectively. Altering normal MN activity, and thus activation of Renshaw cells (RCs) via MN axon collaterals for as little as 10 days during postnatal maturation results in compensatory changes in inhibitory synapses on RCs [4]. Thus altering excitability in one cellular component of the MN-recurrent inhibition loop directly results in alterations in synaptic strength in other components of that circuit. A similar phenomenon appears to be occurring in ALS. From experiments in the SOD1 mouse, embryonic spinal MNs have been shown to be hyperexcitable and to have shorter terminal dendritic branches [5-7] yet roughly 10 days later (postnatal day) P6-11, juvenile spinal MNs display normal excitability, a larger dendritic arborization, and a diminished response to stimulation of sensory afferents [8-11]. In order to understand why SOD1 MN properties are fluctuating during this time, it may be necessary to examine the larger spinal network in which they are maturing. Indeed, many studies suggest glutamate excitotoxicity as a disease mechanism in ALS patients and animal models [12-19]. Conversely, a recent study shows that enhancing excitation in SOD1 mice significantly prolongs lifespan [20]. Perhaps the missing piece in this divergent data is a better understanding of the rest of the network: inhibitory circuits. I propose to exploit the well-characterized connections between MNs, RCs and Ia inhibitory interneurons (IaIINs) [21-23] to examine inhibitory input to MNs in the juvenile SOD1 mouse model. If enhancement of excitatory drive to MNs is beneficial, as [20] suggests, suppression of recurrent inhibition could also hold therapeutic promise.