Collapsin response mediator protein 2, CRMP2, has been identified as an intracellular signaling mediator for Semaphorin 3A (Sema3A). CRMP2 plays a key role in axon guidance, dendritic morphogenesis, and cell polarization. It has been also implicated in a variety of neurological and psychiatric disorders. However, the in vivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2 À/À ) mice. The crmp2 À/À mice showed irregular development of dendritic spines in cortical neurons. The density of dendritic spines was reduced in the cortical layer V pyramidal neurons of crmp2 À/À mice as well as in those of sema3A À/À and crmp1 À/À mice. However, no abnormality was found in dendritic patterning in crmp2 À/À compared to wild-type (WT) neurons. The level of CRMP1 was increased in crmp2, but the level of CRMP2 was not altered in crmp1 À/À compared to WT cortical brain lysates.Dendritic spine density and branching were reduced in double-heterozygous sema3A +/À ;crmp2 +/À and sema3A +/À ;crmp1 +/À mice. The phenotypic defects had no genetic interaction between crmp1 and crmp2. These findings suggest that both CRMP1 and CRMP2 mediate Sema3A signaling to regulate dendritic spine maturation and patterning, but through overlapping and distinct signaling pathways.

Brain damage such as stroke is a devastating neurological condition that may severely compromise patient quality of life. No effective medication-mediated intervention to accelerate rehabilitation has been established. We found that a small compound, edonerpic maleate, facilitated experience-driven synaptic glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptor delivery and resulted in the acceleration of motor function recovery after motor cortex cryoinjury in mice in a training-dependent manner through cortical reorganization. Edonerpic bound to collapsin-response-mediator-protein 2 (CRMP2) and failed to augment recovery in CRMP2-deficient mice. Edonerpic maleate enhanced motor function recovery from internal capsule hemorrhage in nonhuman primates. Thus, edonerpic maleate, a neural plasticity enhancer, could be a clinically potent small compound with which to accelerate rehabilitation after brain damage.

Collapsin response mediator protein 2 (CRMP2) plays a key role in axon guidance, dendritic morphogenesis and cell polarization. CRMP2 is implicated in various neurological and psychiatric disorders. However, in vivo functions of CRMP2 remain unknown. We generated CRMP2 gene-deficient (crmp2 À/À ) mice and examined their behavioral phenotypes. During 24-h home cage monitoring, the activity level during the dark phase of crmp2 À/À mice was significantly higher than that of wild-type (WT) mice. Moreover, the time during the open arm of an elevated plus maze was longer for crmp2 À/À mice than for WT mice. The duration of social interaction was shorter for crmp2 À/À mice than for WT mice. Crmp2 À/À mice also showed mild impaired contextual learning. We then examined the methamphetamine-induced behavioral change of crmp2 À/À mice. Crmp2 À/À mice showed increased methamphetamine-induced ambulatory activity and serotonin release. Crmp2 À/À mice also showed altered expression of proteins involved in GABAergic synapse, glutamatergic synapse and neurotrophin signaling pathways. In addition, SNAP25, RAB18, FABP5, ARF5 and LDHA, which are related genes to schizophrenia and methamphetamine sensitization, are also decreased in crmp2 À/À mice.Our study implies that dysregulation of CRMP2 may be involved in pathophysiology of neuropsychiatric disorders.

Semaphorin 3A (Sema3A), originally identified as a potent growth cone collapsing factor in developing sensory neurons, is now recognized as a key player in immune, cardiovascular, bone metabolism and neurological systems. Here we established an anti-Sema3A monoclonal antibody that neutralizes the effects of Sema3A both in vitro and in vivo. The anti-Sema3A neutralization chick IgM antibodies were screened by combining an autonomously diversifying library selection system and an in vitro growth cone collapse assay. We further developed function-blocking chick-mouse chimeric and humanized anti-Sema3A antibodies. We found that our anti-Sema3A antibodies were effective for improving the survival rate in lipopolysaccharide-induced sepsis in mice. Our antibody is a potential therapeutic agent that may prevent the onset of or alleviate symptoms of human diseases associated with Sema3A.

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