Front Cell Neurosci
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Front Cell Neurosci · Jan 2014
ReviewNeuronal migration and its disorders affecting the CA3 region.
In this review, we focus on CA3 neuronal migration disorders in the rodent. We begin by introducing the main steps of hippocampal development, and we summarize characteristic hippocampal malformations in human. ⋯ We successively describe their molecular, physiological and behavioral phenotypes that together contribute to a better understanding of CA3-dependent functions. We finally discuss potential factors underlying the CA3 vulnerability revealed by these mouse mutants and that may also contribute to other human neurological and psychiatric disorders.
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Front Cell Neurosci · Jan 2014
ReviewNeuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain.
The development of neuropathic pain in response to peripheral nerve lesion for a large part depends on microglia located at the dorsal horn of the spinal cord. Thus the injured nerve initiates a response of microglia, which represents the start of a cascade of events that leads to neuropathic pain development. For long it remained obscure how a nerve injury in the periphery would initiate a microglia response in the dorsal horn of the spinal cord. ⋯ Recent results obtained in transgenic animals clearly show that microglia in vivo do not express CCR2 but that peripheral myeloid cells and neurons do. This suggests that CCL2 expressed by injured dorsal root neurons does not act as neuron-microglia signal in contrast to CCL21. Instead, CCL2 in the injured dorsal root ganglia (DRG) may act as autocrine or paracrine signal and may stimulate first or second order neurons in the pain cascade and/or attract CCR2-expressing peripheral monocytes/macrophages to the spinal cord.
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The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. ⋯ Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression.
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Front Cell Neurosci · Jan 2014
The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth.
Activity-dependent neurite outgrowth is a highly complex, regulated process with important implications for neuronal circuit remodeling in development as well as in seizure-induced sprouting in epilepsy. Recent work has linked outgrowth to collapsin response mediator protein 2 (CRMP2), an intracellular phosphoprotein originally identified as axon guidance and growth cone collapse protein. The neurite outgrowth promoting function of CRMP2 is regulated by its phosphorylation state. ⋯ Knockdown of CRMP2 by siRNA in cortical neurons resulted in reduced CRMP2-dependent neurite outgrowth; incubation with (S)-LCM phenocopied this effect. Other CRMP2-mediated processes were unaffected. (S)-LCM subverted neurite outgrowth not by affecting the canonical CRMP2-tubulin association but rather by impairing the ability of CRMP2 to promote tubulin polymerization, events that are perfunctory for neurite outgrowth. Taken together, these results suggest that changes in the phosphorylation state of CRMP2 are a major contributing factor in activity-dependent regulation of neurite outgrowth.
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Front Cell Neurosci · Jan 2014
Differential neuroprotective potential of CRMP2 peptide aptamers conjugated to cationic, hydrophobic, and amphipathic cell penetrating peptides.
The microtubule-associated axonal specification collapsin response mediator protein 2 (CRMP2) is a novel target for neuroprotection. A CRMP2 peptide (TAT-CBD3) conjugated to the HIV transactivator of transcription (TAT) protein's cationic cell penetrating peptide (CPP) motif protected neurons in the face of toxic levels of Ca(2+) influx leaked in via N-methyl-D-aspartate receptor (NMDAR) hyperactivation. Here we tested whether replacing the hydrophilic TAT motif with alternative cationic (nona-arginine (R9)), hydrophobic (membrane transport sequence (MTS) of k-fibroblast growth factor) or amphipathic (model amphipathic peptide (MAP)) CPPs could be superior to the neuroprotection bestowed by TAT-CBD3. ⋯ Neither peptide altered surface trafficking of NMDARs. Neuroprotection conferred by MTS-CBD3 peptide is likely due to its increased uptake coupled with decreased efflux when compared to TAT-CBD3. Overall, our results demonstrate that altering CPPs can bestow differential neuroprotective potential onto the CBD3 cargo.