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Layer-specific genes reveal a rudimentary laminar pattern in human nodular heterotopia

From the Clinical Epileptology and Experimental Neurophysiology Unit (R.G., L.R., R.F.M., C.F., R.S.), Fondazione I.R.C.C.S., Istituto Neurologico "C. Besta," Milan, Italy; Division of Brain Biology (A.W., T.Y.), National Institute for Basic Biology, Okazaki, Japan; and Epilepsy Surgery Center "C. Munari" (L.T., G.L.R.), Department of Pathology (M.B.), Niguarda Hospital, Milan, Italy.

Address correspondence and reprint requests to Dr. Rita Garbelli, Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta," via Celoria 11, 20133 Milan, Italy garbelli.r{at}istituto-besta.it

Objective: To define distinctive features of nodular heterotopia in specimens derived from drug-resistant patients with epilepsy by evaluating mRNA expression of three different layer-specific markers: Rorβ, Er81, and Nurr1.

Methods: We analyzed the expression profile of these genes, recognized as markers mainly expressed in layer IV for Rorβ, in layer V for Er81, and in layer VI for Nurr1, in surgical samples from 14 epileptic patients, using in situ hybridization. Six patients had subcortical nodular heterotopia and 8 patients were controls. The intrinsic organization of nodular formations and of the overlaying neocortex was assessed.

Results: In all patients, the 3 selected genes showed high cortical laminar specificity. In subcortical nodular heterotopia, the different gene expression profiles revealed a rudimentary laminar organization of the nodules. In the overlaying cortex, fewer cells expressed the 3 genes in the appropriate specific layer as compared to controls.

Conclusions: These data provide new insights into possible ontogenetic mechanisms of nodular heterotopia formation and show the potential role of layer-specific markers to elucidate the neuropathology of malformations of cortical development.

Abbreviations: CP = cortical plate; DIG = digoxigenin; ISH = in situ hybridization; NH = nodular heterotopias; NLS = N-lauroylsarcosine; PPL = primordial plexiform layer; SCH = subcortical heterotopia; SP = subplate; SSC = standard saline citrate.

Supplemental data at www.neurology.org

Editorial, page 742

e-Pub ahead of print on June 17, 2009, at www.neurology.org.

Supported by grants from the Italian Ministry of Health, Associazione Paolo Zorzi, Fondazione Banca del Monte di Lombardia, and EU grant "Functional Genomics and Neurobiology of Epilepsy (EPICURE)" contract LSHM-CT-2006.0373315.

Disclosure: The authors report no disclosures.

Received November 13, 2008. Accepted in final form April 16, 2009.

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