In addition, the presence of atypical AMPA receptors in MNs compared to other neurons might render them more permeable to Ca2+. Functional AMPA receptors normally form a tetrameric structure composed, in various combinations, of the four subunits, GluR1, GluR2, GluR3, and GluR4. The Ca2+ conductance of these receptors differs markedly depending on whether GluR2 is a component of the receptor. However, in MNs, AMPA receptors express proportionately fewer GluR2 subunits relative to other types (Kawahara et al., 2003; Sun et al., 2005), which may render them more permeable to Ca2+ and thus more vulnerable to excitotoxic injury than other cells. Consistent with this notion, more GluR1 and GluR2 subunits are present in oculomotor neurons compared to spinal MNs in humans (Brockington et al., 2013), and treatment with AMPA/kainate of slice preparations from the rat lumbar spinal cord and midbrain results in more Ca2+ influx in spinal cord MNs compared to oculomotor neurons (Brockington et al., 2013). MNs in culture or in vivo are selectively vulnerable to glutamate receptor agonists, particularly those that stimulate AMPA receptors and induce excitotoxicity (Carriedo et al., 1996; Urushitani et al., 1998; Fryer et al., 1999; Van and Robberecht, 2000), whereas NMDA does not damage spinal cord MNs (Curtis and Malik, 1985; Pisharodi and Nauta, 1985; Hugon et al., 1989; Urca and Urca, 1990; Nakamura et al., 1994; Ikonomidou et al., 1996; Kruman et al., 1999). Moreover, ALS-vulnerable α-spinal cord MNs display greater AMPA receptor current density than other spinal neurons (Vandenberghe et al., 2000). Furthermore, when this density is reduced pharmacologically to levels similar to spinal neurons, these MNs are no longer vulnerable to activation of AMPA receptors. Similarly, when mutant SOD1G93A mice are crossed with mice overexpressing the GluR2 subunit in cholinergic neurons, the resulting progeny possess AMPA receptors with reduced permeability to Ca2+ and prolonged survival compared to SOD1G93A mice (Tateno et al., 2004), highlighting the importance of AMPA receptors and GluR2 in ALS.