These events would affect the functionality of the local spinal cord circuitry. A reduced cholinergic input onto Renshaw interneurons may lead to less inhibition of synergic MNs to counteract the powerful effect of PS-341 excitatory
volleys brought about by glutamatergic stimulation. In consequence, MNs rest more vulnerable to excitotoxicity as it is characteristic in ALS (Pieri et al. Inhibitors,research,lifescience,medical 2003; Kuo et al. 2004). Moreover, dysfunction of Renshaw cells may precede the loss of glycinergic synapses onto MNs that was described for this mouse model to occur at symptomatic stage (Chang and Martin 2009). In agreement, alteration of this local circuitry has been also observed in ALS patients that present a decrease in recurrent
inhibition (Raynor and Shefner 1994). Our observations support the hypothesis that stripping of synaptic, in particular cholinergic, contacts with MNs might be one of the earliest events in ALS (Murray et al. 2010). Microglia has been reported Inhibitors,research,lifescience,medical to initiate stripping events (Blinzinger and Kreutzberg 1968), and MHC-I molecules are important for the balanced excitatory/inhibitory Inhibitors,research,lifescience,medical input synaptic withdrawal that normally occurs during development of the nervous system and in the synaptic removal process in axotomized MNs (Schutz 2005; Thams et al. 2008). We observed early activated microglia surrounding MNs concurrent with a loss of MHC-I expression within MNs. As the regenerative capacity is hampered in animals lacking MHC class I signaling (Thams et al. 2008), its early downregulation in the SOD1G93A transgenic mice may influence both the unbalanced
synaptic Inhibitors,research,lifescience,medical stripping and the difficulty in successful regeneration described in the model. The Inhibitors,research,lifescience,medical diminution in cholinergic presynaptic boutons was also extended to changes in the postsynaptic sites, revealed by loss of Sig1-R immunoreactivity, an ion-buffering chaperone present in the subsurface cisternae of MNs underneath presynaptic C-boutons. Undoubtedly, this may influence ion channel conductivity and calcium buffering leading to changes in the pattern of MN firing and to altered motor behavior as that observed in the Sig1-R knockout mice (Mavlyutov et al. 2010). Reinforcing the potential etiopathogenic interest of the Sig1-R alteration is the recent discovery of Sig1-R mutations linked to some cases of MN disease (Luty out et al. 2010). Finally, how can an early and general reduction of cholinergic activity contribute to the different vulnerability observed between fast (more vulnerable) and slow MN types in ALS? One of the possibilities is that requirement of ACh production is markedly different between slow and fast MNs because they diverge in the total number of action potentials fired per day (Hennig and Lomo 1985) and in the amount of ACh released per action potential (quantal content).