Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide (LCM) which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ~8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison to injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCM’s mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting.

Sensory neurons transduce various stimuli including temperature, pain, and touch from the periphery to the central nervous system. Sensory neuron development is governed by a combination of extracellular cues and specific gene expression. We demonstrated that the transcription factor Sox11 was highly expressed in the developing sensory neurons. To test the function of Sox11, we used a knockin mouse model where the entire coding region of Sox11 was replaced by a LacZ reporter. The ablation of Sox11 caused severe reduction in sensory neuron survival in the trigeminal and dorsal root ganglia, although it did not affect migration of neural crest cells or acquisition of major sensory neuron subtypes. We further demonstrated that ablating Sox11 caused an arrest of axonal outgrowth in vivo and in vitro. This defect could not be fully rescued by blocking cell death. Our data suggest that Sox11 is a key regulator of sensory neuron development. Developmental Dynamics 240:52-64,