In Vivo Restoration of Physiological Levels of Truncated TrkB.T1 Receptor Rescues Neuronal Cell Death in a Trisomic Mouse Model

Dorsey, Susan G.; Renn, Cynthia L.; Carim-Todd, Laura; Barrick, Colleen; Bambrick, Linda L.; Krueger, Bruce K.; Ward, Christopher W.; Tessarollo, Lino

doi:10.1016/j.neuron.2006.06.009

Cited by 107 publications

(139 citation statements)

References 48 publications

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“…Our data have shown that astrocytes can be CXCR4 positive but TrkB negative. Moreover, glial cells express the truncated isoform of TrkB (Fryer et al, 1996), which does not appear to mediate most of the neurotrophic effect of BDNF; rather this receptor prevents BDNF signaling (Dorsey et al, 2006). Only detailed anatomical studies will reveal why BDNF has a restricted action on CXCR4 in these areas.…”

Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

et al. 2008

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Chemokine receptors, and in particular CXCR4 and CCR5 play a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV)4 associated dementia (HAD). Thus, new insight into the expression of CXCR4 in the central nervous system may help develop therapeutic compounds against HAD. Brain-derived neurotrophic factor (BDNF) is neuroprotective in vitro against two strains of the HIV envelope protein gp120 that binds to CXCR4 or CCR5. Therefore, we examined whether BDNF modulates chemokine receptor expression in vivo. The content of CXCR4 mRNA and proteins was determined in the cerebral cortex and hippocampus of 6-month-old BDNF heterozygous mice and wild type littermates by using polymerase chain reaction and immunohistochemistry, respectively. BDNF heterozygous mice exhibited an increase in CXCR4 mRNA compared to wild type. Histological analyses revealed an up-regulation of CXCR4 immunoreactivity mainly in neurons. Most of these neurons were positive for TrkB, the BDNF receptor with a tyrosine kinase activity. Increases in CXCR4 mRNA levels were observed in 18-month-old BDNF heterozygous mice but not in 7 day-old mice, suggesting that the modulatory role of BDNF occurs only in mature animals. To determine whether BDNF affects also CXCR4 internalization, SH-SY5Y neuroblastoma cells were exposed to BDNF and cell surface CXCR4 levels were measured at various times. BDNF induced CXCR4 internalization within minutes. Lastly, BDNF heterozygous mice showed higher levels of CCR5 and CXCR3 mRNA than wild type in the cerebral cortex, hippocampus and striatum. Our data indicate that BDNF may modulate the availability of chemokine receptors implicated in HIV infection.

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Section: Discussionmentioning

confidence: 99%

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

et al. 2008

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“…This truncated TrkB is the predominant isoform in the adult hippocampus (Silhol et al, 2005), and interestingly, it has been shown to affect BDNF signaling via specific downstream pathways. Thus, overexpression or loss of TrkB.T1 selectively affects BDNF-mediated Akt activation, but the phosphorylation of ERK is unaffected (Dorsey et al, 2006). As BDNF signaling via Akt but not ERK was altered in Ts1Cje neurons, we studied the expression of the TrkB.T1 isoform using a specific antibody.…”

Section: Intracellular and Secreted Bdnf Are Abnormally Elevated In Tmentioning

confidence: 99%

An Increase in Basal BDNF Provokes Hyperactivation of the Akt-Mammalian Target of Rapamycin Pathway and Deregulation of Local Dendritic Translation in a Mouse Model of Down's Syndrome

Troca-Marín

Alves-Sampaio²,

Montesinos³

2011

Journal of Neuroscience

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As in other diseases associated with mental retardation, dendrite morphology and synaptic plasticity are impaired in Down's syndrome (DS). Both these features of neurons are critically influenced by BDNF, which regulates local dendritic translation through phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (mTOR) and Ras-ERK signaling cascades. Here we show that the levels of BDNF and phosphorylated Akt-mTOR (but not Ras-ERK) pathway proteins are augmented in hippocampal dendrites of Ts1Cje mice, a DS model. Consequently, the rate of local dendritic translation is abnormally high and the modulatory effect of exogenous BDNF is lost. Interestingly, rapamycin (a Food and Drug Administration-approved drug) restores normal levels of phosphorylated Akt-mTOR proteins and normal rates of local translation in Ts1Cje neurons, opening new therapeutic perspectives for DS. The NMDAR inhibitors APV, MK-801, and memantine also restore the normal levels of phospho-mTOR in dendrites of Ts1Cje hippocampal neurons. We propose a model to explain how BDNF-mediated regulation of local translation is lost in the Ts1Cje hippocampus through the establishment of a glutamatergic positive-feedback loop. Together, these findings help elucidate the mechanisms underlying altered synaptic plasticity in DS.

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“…They undergo morphological changes, show enhanced proliferation and migration, and increase synthesis of glial fibrillary acidic protein (GFAP; Silver and Miller, 2004). The glial scar can serve a protective role (Faulkner et al, 2004) but can also limit axon regeneration (Silver and Miller, 2004). Moreover, after SCI or peripheral nerve injuries, such glial changes may contribute to neuropathic pain through the production of selected cytokines, chemokines, and growth factors (Hulsebosch et al, 2009;.…”

Section: Introductionmentioning

confidence: 99%

“…TrkB.T1 binds to BDNF with the same affinity as trkB.FL; however, its short 11 aa intracellular domain lacks the kinase activation component required for classical signal transduction pathways, indicating it may have signaling pathways that are distinct from trkB.FL. TrkB.T1 is the predominant isoform expressed in the adult mammalian nervous system (Middlemas et al, 1991;Klein et al, 1993) and is also the sole isoform expressed by astrocytes (Rose et al, 2003;Dorsey et al, 2006). Although the biological functions of trkB.T1 signaling remain poorly understood (Fenner, 2012), during development, trkB.T1 regulates calcium entry into astrocytes as well as astrocytic morphology via GTPases in primary astrocyte cultures (Rose et al, 2003;Ohira et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…TrkB.T1 is upregulated in multiple injury and disease states, including SCI, amyotrophic lateral sclerosis, Down syndrome, Alzheimer's disease, and HIV-related neuropathic pain (Ferrer et al, 1999;King et al, 2000;Liebl et al, 2001;Dorsey et al, 2002Dorsey et al, , 2006Yanpallewar et al, 2012;. In mouse models of neuropathic pain, including that caused by antiretroviral treatment or hindpaw inflammation, the genetic deletion of trkB.T1 reduced both mechanical and thermal hypersensitivity (Renn et al, 2009), and reduced mechanical hyperesthesia after SCI .…”

Section: Introductionmentioning

confidence: 99%

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Truncated TrkB.T1-Mediated Astrocyte Dysfunction Contributes to Impaired Motor Function and Neuropathic Pain after Spinal Cord Injury

Matyas¹,

O’Driscoll

Yu³

et al. 2017

J. Neurosci.

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Following spinal cord injury (SCI), astrocytes demonstrate long-lasting reactive changes, which are associated with the persistence of neuropathic pain and motor dysfunction. We previously demonstrated that upregulation of trkB.T1, a truncated isoform of the brainderived neurotrophic factor receptor (BDNF), contributes to gliosis after SCI, but little is known about the effects of trkB.T1 on the function of astrocytes. As trkB.T1 is the sole isoform of trkB receptors expressed on astrocytes, we examined the function of trkB.T1-driven astrocytes in vitro and in vivo. Immunohistochemistry showed that trkB.T1 ϩ cells were significantly upregulated 7 d after injury, with sustained elevation in white matter through 8 weeks. The latter increase was predominantly found in astrocytes. TrkB.T1 was also highly expressed by neurons and microglia/macrophages at 7 d after injury and declined by 8 weeks. RNA sequencing of cultured astrocytes derived from trkB.T1 ϩ/ϩ (WT) and trkB.T1 Ϫ/Ϫ (KO) mice revealed downregulation of migration and proliferation pathways in KO astrocytes. KO astrocytes also exhibited slower migration/proliferation in vitro in response to FBS or BDNF compared with WT astrocytes. Reduced proliferation of astrocytes was also confirmed after SCI in astrocyte-specific trkB.T1 KO mice; using mechanical allodynia and pain-related measurements on the CatWalk, these animals also showed reduced hyperpathic responses, along with improved motor coordination. Together, our data indicate that trkB.T1 in astrocytes contributes to neuropathic pain and neurological dysfunction following SCI, suggesting that trkB.T1 may provide a novel therapeutic target for SCI.

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In Vivo Restoration of Physiological Levels of Truncated TrkB.T1 Receptor Rescues Neuronal Cell Death in a Trisomic Mouse Model

Cited by 107 publications

References 48 publications

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain

An Increase in Basal BDNF Provokes Hyperactivation of the Akt-Mammalian Target of Rapamycin Pathway and Deregulation of Local Dendritic Translation in a Mouse Model of Down's Syndrome

Truncated TrkB.T1-Mediated Astrocyte Dysfunction Contributes to Impaired Motor Function and Neuropathic Pain after Spinal Cord Injury

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