The Spared Nerve Injury (SNI) Model of Induced Mechanical Allodynia in Mice

Peripheral neuropathic pain is a severe chronic pain condition which may result from trauma to sensory nerves in the peripheral nervous system. The spared nerve injury (SNI) model induces symptoms of neuropathic pain such as mechanical allodynia i.e. pain due to tactile stimuli that do not normally provoke a painful response [1]

Functional and Structural Changes of the Blood-Nerve-Barrier in Diabetic Neuropathy

The incidence of diabetes mellitus is approaching global epidemic proportions and should be considered a major health-care problem of modern societies in the twenty-first century. Diabetic neuropathy is a common chronic complication of diabetes and, although an adequate glycemic control can reduce the frequency of diabetic neuropathy in type 1 diabetes, the majority of type 2 diabetic patients will develop this complication. The underlying cellular and molecular mechanisms are still poorly understood, preventing the development of effective treatment strategies. However, accumulating evidence suggests that breakdown of the blood-nerve barrier (BNB) plays a pivotal pathophysiological role in diabetic neuropathy. In the present review, we highlight the structural and functional significance of the BNB in health and disease, focusing on the pathological molecular events leading to BNB dysfunction in diabetic neuropathy. In addition, we discuss potential molecular targets involved in BNB homeostasis that may pave the way toward novel therapeutic strategies for treating diabetic neuropathy

SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFR alpha 1 and RET

Peer reviewe

Sortilin-related receptor SORCS3 is a postsynaptic modulator of synaptic depression and fear extinction.

SORCS3 is an orphan receptor of the VPS10P domain receptor family, a group of sorting and signaling receptors central to many pathways in control of neuronal viability and function. SORCS3 is highly expressed in the CA1 region of the hippocampus, but the relevance of this receptor for hippocampal activity remained absolutely unclear. Here, we show that SORCS3 localizes to the postsynaptic density and that loss of receptor activity in gene-targeted mice abrogates NMDA receptor-dependent and -independent forms of long-term depression (LTD). Consistent with a loss of synaptic retraction, SORCS3-deficient mice suffer from deficits in behavioral activities associated with hippocampal LTD, particularly from an accelerated extinction of fear memory. A possible molecular mechanism for SORCS3 in synaptic depression was suggested by targeted proteomics approaches that identified the ability of SORCS3 to functionally interact with PICK1, an adaptor that sorts glutamate receptors at the postsynapse. Faulty localization of PICK1 in SORCS3-deficient neurons argues for altered glutamate receptor trafficking as the cause of altered synaptic plasticity in the SORCS3-deficient mouse model. In conclusion, our studies have identified a novel function for VPS10P domain receptors in control of synaptic depression and suggest SORCS3 as a novel factor modulating aversive memory extinction

Normal paired-pulse facilitation in SORCS3-deficient mice.

<p>(<b>A</b>) Representative traces of fEPSPs after paired pulses with increasing interpulse intervals are depicted for the indicated genotypes and conditions. Scale bars: 0.3 mV/20 ms. (<b>B</b>) Paired-pulse facilitation (PPF) was calculated as the ratio of the second fEPSP slope to the first fEPSP slope and plotted at different interstimulus intervals. No significant differences (p>0.05) at any interstimulus intervals were seen comparing <i>Sorcs3</i>^<i>+/+</i> and <i>Sorcs3</i>^<i>-/-</i> mice. Application of the GABA_B receptor agonist baclofen increased the PPF ratio equally in mice of both genotypes. Note that y-axis starts at 100%. Data are given as mean ± SEM.</p

Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury

Peripheral nerve regeneration relies on the ability of Schwann cells to support the regrowth of damaged axons. Schwann cells re-differentiate when reestablishing contact with the sprouting axons, with large fibers becoming remyelinated and small nociceptive fibers ensheathed and collected into Remak bundles. We have previously described how the receptor sortilin facilitates neurotrophin signaling in peripheral neurons via regulated trafficking of Trk receptors. This study aims to characterize the effects of sortilin deletion on nerve regeneration following sciatic crush injury. We found that Sort1(-)(/)(-) mice displayed functional motor recovery like that of WT mice, with no detectable differences in relation to nerve conduction velocities and morphological aspects of myelinated fibers. In contrast, we found abnormal ensheathment of regenerated C-fibers in injured Sort1(-)(/)(-) mice, demonstrating a role of sortilin for Remak bundle formation following injury. Further studies on Schwann cell signaling pathways showed a significant reduction of MAPK/ERK, RSK, and CREB phosphorylation in Sort1(-)(/)(-) Schwann cells after stimulation with neurotrophin-3 (NT-3), while Schwann cell migration and myelination remained unaffected. In conclusion, our results demonstrate that loss of sortilin blunts NT-3 signaling in Schwann cells which might contribute to the impaired Remak bundle regeneration after sciatic nerve injury

Generation and histological analysis of a SORCS3-deficient mouse model.

<p>(<b>A</b>) For targeted disruption of the murine <i>Sorcs3</i> locus, a targeting vector was constructed introducing the neomycin phosphotransferase gene driven by the phosphoglycerate kinase promoter (PGK-neoR) into intron 2 of the <i>Sorcs3</i> locus. The PGK-neoR cassette was flanked by FRT sites (open triangles). In addition, the vector introduced two loxP recombination sites (closed triangles) 5’ and 3’ of exon 1, respectively. Following standard homologous recombination in embryonic stem cells and blastocyst injections, mice carrying the modified gene through the germ line were bred with the flp deleter strain to remove PGK-neoR (targeted allele). For gene inactivation, mice were crossed with cre deleter mice to excise exon 1 that encodes the start codon and signal and pro-peptides of <i>Sorcs3</i> (deleted allele). (<b>B</b>) RT-PCR analysis on brain tissue documents complete loss of transcripts encoding exon 1 in <i>Sorcs3</i>^<i>-/-</i> animals as compared to <i>Sorcs3</i>^<i>+/+</i> controls. Minor amounts of an aberrant transcript encompassing exons 13-15 are seen. (C) Successful ablation of SORCS3 protein expression was confirmed by Western blot analysis of extracts from hippocampus (Hip), cortex (Ctx), and cerebellum (Cer) detecting SORCS3 in wild type mice (+/+), but in animals homozygous for the disrupted allele (-/-). Detection of Na⁺/K⁺ ATPase α-1 subunit (Na/K) served as loading control. (<b>D</b>) Histological sections stained with Nissl from hippocampi of <i>Sorcs3</i>^<i>+/+</i> and <i>Sorcs3</i>^<i>-/-</i> mice. (<b>E</b>) Western blot analysis of the indicated proteins in the PSD fraction of hippocampi from <i>Sorcs3</i>^<i>+/+</i> and <i>Sorcs3</i>^<i>-/-</i> mice. NR_1/2B, NMDA glutamate receptor subunit 1/2B; GluR1/2, AMPA glutamate receptor subunit 1/2; mGlur5, metabotropic glutamate receptor type 5; p75NTR, nerve growth factor receptor; TrkB, neurotrophic tyrosine kinase, receptor, type 2.</p