Figure 5.

Proposed neurobiological model for maladaptive spinal plasticity. The uncontrollable stimulation-induced spinal learning deficit requires the activation of group I metabotropic glutamate receptors and the substance P receptor NK1R which liberate intracellular calcium (Baumbauer et al., 2008; Ferguson et al., 2008a). This in turn activates downstream protein kinases PKC and CamKII, (Ferguson et al., 2006, 2008a; Baumbauer et al., 2007). These kinases are known to produce long-term alterations in ionotropic glutamate receptor (iGluR) function; however, the specific role of this signaling cascade in spinal learning remains an open question (“?”; dashed lines). Altered iGluR activation is known to further increase post-synaptic calcium levels through the NMDA receptor channel and calcium-permeable AMPA receptors, which may provide a mechanism for altered associative learning in the spinal cord. Increases in intracellular calcium can induce further protein kinase activity and de novo protein synthesis, all of which have all been shown necessary for the development of the stimulation-induced spinal learning deficit (Patton et al., 2004; Baumbauer et al., 2006; Huie et al., 2012a). Well-characterized features are shown in black. Areas of ongoing study are shown in red. Adapted from Ferguson et al. (2008a).