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Xianhua Piao - One of the best experts on this subject based on the ideXlab platform.
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g protein coupled receptor 56 and collagen iii a receptor ligand pair regulates Cortical development and lamination
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Sung Jin Jeong, Natalie Strokes, Shihong Li, Xianhua PiaoAbstract:GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in Cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates Cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like Cortical Malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα12/13 family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.
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gpr56 regulates pial basement membrane integrity and Cortical lamination
The Journal of Neuroscience, 2008Co-Authors: Shihong Li, Samir Koirala, Gabriel Corfas, Lei Xu, Richard O Hynes, Lihong Bu, Xianhua PiaoAbstract:GPR56 is a member of the family of adhesion G-protein-coupled receptors that have a large extracellular region containing a GPS (G-protein proteolytic site) domain. Loss-of-function mutations in the GPR56 gene cause a specific human brain Malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is a radiological diagnosis and its histopathology remains unclear. This study demonstrates that loss of the mouse Gpr56 gene leads to neuronal ectopia in the cerebral cortex, a cobblestone-like Cortical Malformation. There are four crucial events in the development of cobblestone cortex, namely defective pial basement membrane (BM), abnormal anchorage of radial glial endfeet, mislocalized Cajal–Retzius cells, and neuronal overmigration. By detailed time course analysis, we reveal that the leading causal events are likely the breaches in the pial BM. We show further that GPR56 is present in abundance in radial glial endfeet. Furthermore, a putative ligand of GPR56 is localized in the marginal zone or overlying extracellular matrix. These observations provide compelling evidence that GPR56 functions in regulating pial BM integrity during Cortical development.
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bilateral generalized polymicrogyria bgp a distinct syndrome of Cortical Malformation
Neurology, 2004Co-Authors: Xianhua Piao, Adria Bodell, Meral Topçu, C Giannini, Gregory D Cascino, Ingrid E Scheffer, C G Woods, K Tezcan, Richard J LeventerAbstract:Background: Syndromes of bilateral symmetric polymicrogyria include an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), in which the Malformation is most severe rostrally. The authors describe a new syndrome they have termed “bilateral generalized polymicrogyria” (BGP), in which the Malformation occurs in a generalized distribution but is often most severe in the perisylvian regions. Methods: Patients with bilateral polymicrogyria were identified from multiple medical centers worldwide. The diagnosis of BGP was based on findings from conventional spin echo MRI and, in one case, postmortem neuropathologic findings. Genetic analysis was performed for those patients from consanguineous pedigrees and those with multiple affected siblings to rule out linkage to the BFPP locus on chromosome 16q. Results: Twelve patients were identified with BGP. Clinical features included cognitive and motor delay as well as seizures. Some specific features characteristic of other known bilateral polymicrogyria syndromes, such as pseudobulbar palsy and dysconjugate gaze, were not commonly seen in these patients. Radiologically, polymicrogyria appeared widespread but was often most severe in the perisylvian regions. Pathologic examination in one case revealed a diffusely thin and excessively folded cerebral cortex lacking normal six-layered architecture. Seven patients subjected to genetic analysis did not demonstrate linkage to the BFPP locus. Conclusions: BGP is a distinct syndrome of Cortical Malformation. Several features allow BGP to be distinguished from other disorders on the growing list of bilateral symmetric polymicrogyria syndromes.
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g protein coupled receptor dependent development of human frontal cortex
Science, 2004Co-Authors: Xianhua Piao, Adria Bodell, Lina Baselvanagaite, Rachel Straussberg, William B Dobyns, Sean S Hill, Bernard S Chang, Bassam Qasrawi, Robin M Winter, Micheil A InnesAbstract:The mammalian cerebral cortex is characterized by complex patterns of anatomical and functional areas that differ markedly between species, but the molecular basis for this functional subdivision is largely unknown. Here, we show that mutations in GPR56, which encodes an orphan G protein-coupled receptor (GPCR) with a large extracellular domain, cause a human brain Cortical Malformation called bilateral frontoparietal polymicrogyria (BFPP). BFPP is characterized by disorganized Cortical lamination that is most severe in frontal cortex. Our data suggest that GPCR signaling plays an essential role in regional development of human cerebral cortex.
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an autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12 2 21
American Journal of Human Genetics, 2002Co-Authors: Xianhua Piao, Lina Baselvanagaite, Rachel Straussberg, Ellen P Grant, Elizabeth W Pugh, Kim Doheny, Betty Q Doan, Susan E HongAbstract:Polymicrogyria is a cerebral Cortical Malformation that is grossly characterized by excessive Cortical folding and microscopically characterized by abnormal Cortical layering. Although polymicrogyria appears to have one or more genetic causes, no polymicrogyria loci have been identified. Here we describe the clinical and radiographic features of a new genetic form of polymicrogyria and localize the responsible gene. We studied two consanguineous Palestinian pedigrees with an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), using linkage analysis. Five affected children had moderate-to-severe mental retardation, developmental delay, and esotropia, and four of the five affected children developed seizures. Brain magnetic-resonance imaging revealed polymicrogyria that was most prominent in the frontal and parietal lobes but involved other Cortical areas as well. A genomewide linkage screen revealed a single locus that was identical by descent in affected children in both families and showed a single disease-associated haplotype, suggesting a common founder mutation. The locus for BFPP maps to chromosome 16q12.2-21, with a minimal interval of 17 cM. For D16S514, the maximal pooled two-point LOD score was 3.98, and the maximal multipoint LOD score was 4.57. This study provides the first genetic evidence that BFPP is an autosomal recessive disorder and serves as a starting point for the identification of the responsible gene.
Richard J Leventer - One of the best experts on this subject based on the ideXlab platform.
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eml1 associated brain overgrowth syndrome with ribbon like heterotopia
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2019Co-Authors: Renske Oegema, George Mcgillivray, Richard J Leventer, Annegaelle Le Moing, Nadia Bahibuisson, Angela Barnicoat, Simone MandelstamAbstract:EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain Malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subCortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like Cortical Malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain Malformations, severe developmental delay, seizures and visual impairment.
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the histopathology of polymicrogyria a series of 71 brain autopsy studies
Developmental Medicine & Child Neurology, 2016Co-Authors: Anna C Jansen, Richard J Leventer, Yves Robitaille, Mrinalini Honavar, Nandini Mullatti, Eva Andermann, Frederick Andermann, Waney SquierAbstract:Aim Polymicrogyria (PMG) is one of the most common forms of Cortical Malformation yet the mechanism of its development remains unknown. This study describes the histopathological aspects of PMG in a large series including a significant proportion of fetal cases. Method We have reviewed the neuropathology and medical records of 44 fetuses and 27 children and adults in whom the Cortical architecture was focally or diffusely replaced by one or more festooning bands of neurons. Results The pial surface of the brain overlying the polymicrogyric cortex was abnormal in almost 90% of cases irrespective of the aetiology. This accords with animal studies indicating the importance of the leptomeninges in Cortical development. The aetiology of PMG was highly heterogeneous and there was no correlation between Cortical layering patterns and aetiology. PMG was almost always associated with other brain Malformations. Interpretation The inclusion of many fetal cases has allowed us to examine the early developmental stages of PMG. The study indicates the significance of surface signals responsible for human corticogenesis and the complex interaction between genetic and environmental factors leading to this common endpoint of Cortical maldevelopment.
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polymicrogyria a common and heterogeneous Malformation of Cortical development
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2014Co-Authors: Chloe Stutterd, Richard J LeventerAbstract:Polymicrogyria (PMG) is one of the most common Malformations of Cortical development. It is characterized by overfolding of the cerebral cortex and abnormal Cortical layering. It is a highly heterogeneous Malformation with variable clinical and imaging features, pathological findings, and etiologies. It may occur as an isolated Cortical Malformation, or in association with other Malformations within the brain or body as part of a multiple congenital anomaly syndrome. Polymicrogyria shows variable topographic patterns with the bilateral perisylvian pattern being most common. Schizencephaly is a subtype of PMG in which the overfolded cortex lines full-thickness clefts connecting the subarachnoid space with the cerebral ventricles. Both genetic and non-genetic causes of PMG have been identified. Non-genetic causes include congenital cytomegalovirus infection and in utero ischemia. Genetic causes include metabolic conditions such as peroxisomal disorders and the 22q11.2 and 1p36 continguous gene deletion syndromes. Mutations in over 30 genes have been found in association with PMG, especially mutations in the tubulin family of genes. Mutations in the (PI3K)-AKT pathway have been found in association PMG and megalencephaly. Despite recent genetic advances, the mechanisms by which polymicrogyric cortex forms and causes of the majority of cases remain unknown, making diagnostic and prenatal testing and genetic counseling challenging. This review summarizes the clinical, imaging, pathologic, and etiologic features of PMG, highlighting recent genetic advances.
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bilateral posterior periventricular nodular heterotopia a recognizable Cortical Malformation with a spectrum of associated brain abnormalities
American Journal of Neuroradiology, 2013Co-Authors: Simone Mandelstam, George Mcgillivray, Richard J Leventer, Renzo Guerrini, A Sandow, M Van Kogelenberg, Stephen P Robertson, Samuel F Berkovic, Graeme D Jackson, Ingrid E SchefferAbstract:BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex Malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain Malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA . RESULTS: Nodules were often noncontiguous ( n = 28) and asymmetric ( n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar Malformations and posterior fossa cysts ( n = 38). Corpus callosum abnormalities ( n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased ( n = 22), and colpocephaly was frequent ( n = 26). Most ( n = 40) had associated Cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common ( n = 27), and hippocampal abnormalities were frequent ( n = 37). Four family cases were identified—2 with concordant Malformation patterns and 2 with discordant Malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian Malformations involving the posterior cerebral and hindbrain structures. DHPLC : denaturing high-performance liquid chromatography FLNA : Filamin A gene PNH : periventricular nodular heterotopia
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bilateral generalized polymicrogyria bgp a distinct syndrome of Cortical Malformation
Neurology, 2004Co-Authors: Xianhua Piao, Adria Bodell, Meral Topçu, C Giannini, Gregory D Cascino, Ingrid E Scheffer, C G Woods, K Tezcan, Richard J LeventerAbstract:Background: Syndromes of bilateral symmetric polymicrogyria include an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), in which the Malformation is most severe rostrally. The authors describe a new syndrome they have termed “bilateral generalized polymicrogyria” (BGP), in which the Malformation occurs in a generalized distribution but is often most severe in the perisylvian regions. Methods: Patients with bilateral polymicrogyria were identified from multiple medical centers worldwide. The diagnosis of BGP was based on findings from conventional spin echo MRI and, in one case, postmortem neuropathologic findings. Genetic analysis was performed for those patients from consanguineous pedigrees and those with multiple affected siblings to rule out linkage to the BFPP locus on chromosome 16q. Results: Twelve patients were identified with BGP. Clinical features included cognitive and motor delay as well as seizures. Some specific features characteristic of other known bilateral polymicrogyria syndromes, such as pseudobulbar palsy and dysconjugate gaze, were not commonly seen in these patients. Radiologically, polymicrogyria appeared widespread but was often most severe in the perisylvian regions. Pathologic examination in one case revealed a diffusely thin and excessively folded cerebral cortex lacking normal six-layered architecture. Seven patients subjected to genetic analysis did not demonstrate linkage to the BFPP locus. Conclusions: BGP is a distinct syndrome of Cortical Malformation. Several features allow BGP to be distinguished from other disorders on the growing list of bilateral symmetric polymicrogyria syndromes.
Renzo Guerrini - One of the best experts on this subject based on the ideXlab platform.
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bilateral posterior periventricular nodular heterotopia a recognizable Cortical Malformation with a spectrum of associated brain abnormalities
American Journal of Neuroradiology, 2013Co-Authors: Simone Mandelstam, George Mcgillivray, Richard J Leventer, Renzo Guerrini, A Sandow, M Van Kogelenberg, Stephen P Robertson, Samuel F Berkovic, Graeme D Jackson, Ingrid E SchefferAbstract:BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex Malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain Malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA . RESULTS: Nodules were often noncontiguous ( n = 28) and asymmetric ( n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar Malformations and posterior fossa cysts ( n = 38). Corpus callosum abnormalities ( n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased ( n = 22), and colpocephaly was frequent ( n = 26). Most ( n = 40) had associated Cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common ( n = 27), and hippocampal abnormalities were frequent ( n = 37). Four family cases were identified—2 with concordant Malformation patterns and 2 with discordant Malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian Malformations involving the posterior cerebral and hindbrain structures. DHPLC : denaturing high-performance liquid chromatography FLNA : Filamin A gene PNH : periventricular nodular heterotopia
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polymicrogyria and deletion 22q11 2 syndrome window to the etiology of a common Cortical Malformation
American Journal of Medical Genetics Part A, 2006Co-Authors: Nathaniel H Robin, Clare Taylor, Donna M Mcdonaldmcginn, Elaine H Zackai, Peter M Bingham, Kevin J Collins, Dawn Earl, Deepak Gill, Tiziana Granata, Renzo GuerriniAbstract:Several brain Malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the Cortical Malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain Malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain Malformation associated with DEL22q11. © 2006 Wiley-Liss, Inc.
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polymicrogyria and deletion 22q11 2 syndrome window to the etiology of a common Cortical Malformation
American Journal of Medical Genetics Part A, 2006Co-Authors: Nathaniel H Robin, Clare Taylor, Donna M Mcdonaldmcginn, Elaine H Zackai, Peter M Bingham, Deepak Gill, Tiziana Granata, Kevin Collins, Dawn L Earl, Renzo GuerriniAbstract:Several brain Malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the Cortical Malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain Malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain Malformation associated with DEL22q11.
Chris G Dulla - One of the best experts on this subject based on the ideXlab platform.
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α2δ 1 signaling drives cell death synaptogenesis circuit reorganization and gabapentin mediated neuroprotection in a model of insult induced Cortical Malformation
eNeuro, 2017Co-Authors: Lauren A Lau, Farzad Noubary, Dongqing Wang, Chris G DullaAbstract:Developmental Cortical Malformations (DCMs) result from pre- and perinatal insults, as well as genetic mutations. Hypoxia, viral infection, and traumatic injury are the most common environmental causes of DCMs, and are associated with the subsyndromes focal polymicrogyria and focal Cortical dysplasia (FCD) Type IIId, both of which have a high incidence of epilepsy. Understanding the molecular signals that lead to the formation of a hyperexcitable network in DCMs is critical to devising novel treatment strategies. In a previous study using the freeze-lesion (FL) murine model of DCM, we found that levels of thrombospondin (TSP) and the calcium channel auxiliary subunit α2δ-1 were elevated. TSP binds to α2δ-1 to drive the formation of excitatory synapses during development, suggesting that overactivation of this pathway may lead to exuberant excitatory synaptogenesis and network hyperexcitability seen in DCMs. In that study, antagonizing TSP/α2δ-1 signaling using the drug gabapentin (GBP) reduced many FL-induced pathologies. Here, we used mice with a genetic deletion of α2δ-1 to determine how α2δ-1 contributes to cell death, elevated excitatory synapse number, and in vitro network function after FL and to examine the molecular specificity of GBP's effects. We identified a critical role for α2δ-1 in FL-induced pathologies and in mediating the neuroprotective effects of GBP. Interestingly, genetic deletion of α2δ-1 did not eliminate GBP's effects on synaptogenesis, suggesting that GBP can have α2δ-1-independent effects. Taken together these studies suggests that inhibiting α2δ-1 signaling may have therapeutic promise to reduce cell death and network reorganization associated with insult-induced DCMs.
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astrocyte membrane properties are altered in a rat model of developmental Cortical Malformation but single cell astrocytic glutamate uptake is robust
Neurobiology of Disease, 2016Co-Authors: Elizabeth Hanson, Niels C Danbolt, Chris G DullaAbstract:Developmental Cortical Malformations (DCMs) are linked with severe epilepsy and are caused by both genetic and environmental insults. DCMs include several neurological diseases, such as focal Cortical dysplasia, polymicrogyria, schizencephaly, and others. Human studies have implicated astrocyte reactivity and dysfunction in the pathophysiology of DCMs, but their specific role is unknown. As astrocytes powerfully regulate glutamate neurotransmission, and glutamate levels are known to be increased in human epileptic foci, understanding the role of astrocytes in the pathological sequelae of DCMs is extremely important. Additionally, recent studies examining astrocyte glutamate uptake in DCMs have reported conflicting results, adding confusion to the field. In this study we utilized the freeze lesion (FL) model of DCM, which is known to induce reactive astrocytosis and cause significant changes in astrocyte morphology, proliferation, and distribution. Using whole-cell patch clamp recording from astrocytes, we recorded both UV-uncaging and synaptically evoked glutamate transporter currents (TCs), widely accepted assays of functional glutamate transport by astrocytes. With this approach, we set out to test the hypothesis that astrocyte membrane properties and glutamate transport were disrupted in this model of DCM. Though we found that the developmental maturation of astrocyte membrane resistance was disrupted by FL, glutamate uptake by individual astrocytes was robust throughout FL development. Interestingly, using an immunolabeling approach, we observed spatial and developmental differences in excitatory amino acid transporter (EAAT) expression in FL cortex. Spatially specific differences in EAAT2 (GLT-1) and EAAT1 (GLAST) expression suggest that the relative contribution of each EAAT to astrocytic glutamate uptake may be altered in FL cortex. Lastly, we carefully analyzed the amplitudes and onset times of both synaptically- and UV uncaging-evoked TCs. We found that in the FL cortex, synaptically-evoked, but not UV uncaging-evoked TCs, were larger in amplitude. Additionally, we found that the amount of electrical stimulation required to evoke a synaptic TC was significantly reduced in the FL cortex. Both of these findings are consistent with increased excitatory input to the FL cortex, but not with changes in how individual astrocytes remove glutamate. Taken together, our results demonstrate that the maturation of astrocyte membrane resistance, local distribution of glutamate transporters, and glutamatergic input to the cortex are altered in the FL model, but that single-cell astrocytic glutamate uptake is robust.
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gabapentin attenuates hyperexcitability in the freeze lesion model of developmental Cortical Malformation
Neurobiology of Disease, 2014Co-Authors: Lauren Andresen, David Hampton, Amaro Taylorweiner, Lydie Morel, Yongjie Yang, Jamie Maguire, Chris G DullaAbstract:Developmental Cortical Malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, Cortical Malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro Cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/α2δ-1 signaling has been shown to drive the formation of excitatory synapses during Cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental Cortical Malformations.
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glutamate biosensor imaging reveals dysregulation of glutamatergic pathways in a model of developmental Cortical Malformation
Neurobiology of Disease, 2013Co-Authors: Chris G Dulla, Hiroaki Tani, Julia Brill, Richard J Reimer, John R HuguenardAbstract:Cortical Malformations can cause intractable epilepsy, but the underlying epileptogenic mechanisms are poorly understood. We used high-speed glutamate biosensor imaging to ask how glutamatergic signaling is altered in Cortical Malformations induced by neonatal freeze-lesions (FL). In non-lesion neoCortical slices from 2 to 8week old rats, evoked glutamate signals were symmetrical in the medio-lateral axis and monotonic, correlating with simple, brief (≈50ms) local field potentials (LFPs). By contrast, in FL cortex glutamate signals were prolonged, increased in amplitude, and polyphasic, which paralleled a prolongation of the LFP. Using glutamate biosensor imaging, we found that glutamate signals propagated throughout large areas of FL cortex and were asymmetric (skewed toward the lesion). Laminar analysis demonstrated a shift in the region of maximal glutamate release toward superficial layers in FL cortex. The ability to remove exogenous glutamate was increased within the FL itself but was decreased in immediately adjacent regions. There were corresponding alterations in astrocyte density, with an increase within the lesion and a decrease in deep Cortical layers surrounding the lesion. These findings demonstrate both network connectivity and glutamate metabolism are altered in this Cortical Malformation model and suggests that the regional ability of astrocytes to remove released glutamate may be inversely related to local excitability.
Nathaniel H Robin - One of the best experts on this subject based on the ideXlab platform.
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polymicrogyria and deletion 22q11 2 syndrome window to the etiology of a common Cortical Malformation
American Journal of Medical Genetics Part A, 2006Co-Authors: Nathaniel H Robin, Clare Taylor, Donna M Mcdonaldmcginn, Elaine H Zackai, Peter M Bingham, Kevin J Collins, Dawn Earl, Deepak Gill, Tiziana Granata, Renzo GuerriniAbstract:Several brain Malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the Cortical Malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain Malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain Malformation associated with DEL22q11. © 2006 Wiley-Liss, Inc.
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polymicrogyria and deletion 22q11 2 syndrome window to the etiology of a common Cortical Malformation
American Journal of Medical Genetics Part A, 2006Co-Authors: Nathaniel H Robin, Clare Taylor, Donna M Mcdonaldmcginn, Elaine H Zackai, Peter M Bingham, Deepak Gill, Tiziana Granata, Kevin Collins, Dawn L Earl, Renzo GuerriniAbstract:Several brain Malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the Cortical Malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain Malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain Malformation associated with DEL22q11.
