Mouse pups lacking collapsin response mediator protein 4 manifest impaired olfactory function and hyperactivity in the olfactory bulb

Abstract

Members of the collapsin response mediator protein (CRMP) family are reported to be involved in the pathogenesis of various neuronal disorders, including schizophrenia and autism. One of them, CRMP4, is reported to participate in aspects of neuronal development, such as axonal guidance and dendritic development. However, no physiological or behavioral phenotypes in Crmp4 knockout (Crmp4-KO) mice have been identified, making it difficult to elucidate the in vivo roles of CRMP4. Focusing on the olfaction process because of the previous study showing strong expression of Crmp4 mRNA in the olfactory bulb (OB) during the early postnatal period, it was aimed to test the hypothesis that Crmp4-KO pups would exhibit abnormal olfaction. Based on measurements of their ultrasonic vocalizations, impaired olfactory ability in Crmp4-KO pups was found. In addition, c-Fos expression, a marker of neuron activity, revealed hyperactivity in the OB of Crmp4-KO pups compared with wild-types following exposure to an odorant. Moreover, the mRNA and protein expression levels of glutamate receptor 1 (GluR1) and 2 (GluR2) were exaggerated in Crmp4-KO pups relative to other excitatory and inhibitory receptors and transporters, raising the possibility that enhanced expression of these excitatory receptors contributes to the hyperactivity phenotype and impairs olfactory ability. This study provides evidence for an animal model for elucidating the roles of CRMP4 in the development of higher brain functions as well as for elucidating the developmental regulatory mechanisms controlling the activity of the neural circuitry.

Hierarchical CRMP2 posttranslational modifications control NaV1.7 function

“…For instance, CRMP4 expression increases following sciatic nerve axotomy (38), and a CRMP2-CRMP4 tetramer may permit binding to NaV1.7, but not other NaV1.x channels. CRMP4-KO mice exhibit impaired olfactory ability (39), and loss-of-function mutations in NaV1.7 cause anosmia (40), thus providing further evidence of a possible link between CRMP4 and NaV1.7. However, another possibility is that there may be a still unknown protein that is required for the CRMP2-NaV1.7 specificity.…”

Blocking CRMP2 SUMOylation reverses neuropathic pain

“…However, mice lacking CRMP4 manifest impaired olfactory function and hyperactivity in the olfactory bulb and have increased levels of ionotropic glutamate receptors GluRs 1 and 2, which have been implicated in autism spectrum disorders and schizophrenia. 14 CRMP5 knockout mice implicate this protein in dendritic development and synaptic plasticity in cerebellar purkinje cells, 15 and CRMP5 autoantibodies were reported in patients with paraneoplastic neurological syndrome characterized by cerebellar ataxia and chorea. Therefore, understanding CRMP signaling has significant clinical implications.…”

CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury

“…In Crmp4−/− mice, proximal bifurcation of CA1 hippocampal pyramidal neurons were seen in the same manner as in Sema3a−/− mice [56] and p35−/− mice, a Cdk5 activator [57]. Tissue structure abnormalities and neuronal hyperactivity due to the enhanced dendritic growth of mitral cells in the olfactory bulb was also observed in Crmp4−/− mice [58,59]. Likewise, a decrease in axon growth of hippocampal neurons was also seen in Crmp4−/− mice [60].…”

“…Crmp4-/-Increased proximal bifurcation of CA1 pyramidal neurons [57] Axon growth and motor and sensory recovery after SCI [41,88] Enhanced dendritic growth and hyperactivity in olfactory bulb neurons [58,59] Reduced apoptosis, inflammation, and scar formation [41] Decrease in axon extension and growth cone formation [60] Delayed dopaminergic neuron death in the PD model [43] …”

“…For example, in Crmp4−/− mice, enhanced dendrite growth results in the hyperactivity of neurons in the olfactory bulb [58,59], and reduced spine density is observed in Crmp2KI/KI mice [50]. Likewise, the increase in the amount of dopamine secreted in Crmp1−/− mice leads to hyperactivity-exhibiting a neuropsychiatric disease-like phenotype.…”