Neurobiology of disease
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Neurobiology of disease · Jan 2015
Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury.
Extracellular matrix molecule chondroitin sulfate proteoglycans (CSPGs) are highly upregulated in scar tissues and form a potent chemical barrier for CNS axon regeneration. Recent studies support that the receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member leukocyte common antigen related phosphatase (LAR) act as transmembrane receptors to mediate CSPG inhibition. PTPσ deficiency increased regrowth of ascending axons into scar tissues and descending corticospinal tract (CST) axons into the caudal spinal cord after spinal cord injury (SCI). ⋯ LAR protein was upregulated days to weeks after injury and co-localized to serotonergic and CST axons. Moreover, LAR deletion improved functional recovery by increasing BMS locomotor scores and stride length and reducing grid walk errors. This is the first transgenic study that demonstrates the crucial role of LAR in restricting regrowth of injured CNS axons.
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Neurobiology of disease · Jan 2015
Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. ⋯ Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.
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Neurobiology of disease · Jan 2015
Diet, age, and prior injury status differentially alter behavioral outcomes following concussion in rats.
Mild traumatic brain injury (mTBI) or concussion affects a large portion of the population and although many of these individuals recover completely, a small subset of people experience lingering symptomology and poor outcomes. Little is known about the factors that affect individual susceptibility or resilience to poor outcomes after mTBI and there are currently no biomarkers to delineate mTBI diagnosis or prognosis. Based upon the growing literature associated with caloric intake and altered neurological aging and the ambiguous link between repetitive mTBI and progressive neurodegeneration, the current study was designed to examine the effect of a high fat diet (HFD), developmental age, and repetitive mTBI on behavioral outcomes following a mTBI. ⋯ Exposure to the high fat diet exacerbated many of the behavioral deficits associated with concussion. Finally, telomere length was shortened following mTBI and was influenced by the animal's dietary intake. Diet, age at the time of injury, and the number of prior concussion incidents differentially contribute to behavioral deficits and may help explain individual variations in susceptibility and resilience to poor outcomes following an mTBI.
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Neurobiology of disease · Jan 2015
BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation.
The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. ⋯ Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury.
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Neurobiology of disease · Jan 2015
Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing.
Mutations in the Gjb2 gene, which encodes a gap junction protein connexin26 (Cx26), are the most prevalent form of hereditary deafness in humans and represent about half of non-syndromic congenital deafness cases in many ethnic populations. Cochlear potassium (K+) recycling in mature cochlea is required for normal hearing. It is thought that gap junctions are essential for K+ recycling and that Gjb2 mutations cause Gjb2-associated deafness by disrupting K+ recycling in mature cochlea. ⋯ Similar amount of Cx26 reduction in more mature cochleae had a much weaker effect in damaging the hearing sensitivity. Our findings indicated that Cx26 plays essential roles in the maturation process of the organ of Corti prior to the establishment of high K+ in the endolymph and the onset of hearing. These results suggest that successful treatment of Cx26 deafness requires early intervention before the cochlea fully matures.