Altered spatial distribution of PV‐cortical cells and dysmorphic neurons in the somatosensory cortex of BCNU‐treated rat model of cortical dysplasia

Abstract

SUMMARYPurpose: Cortical dysplasia (CD) represents a wide range of histopathological abnormalities of the cortical mantle that are frequently associated with drug-resistant epilepsy. Recently, carmustine (1-3-bis-chloroethyl-nitrosurea [BCNU]), given to pregnant rats on embryonic day (E) 15, has been used to develop an experimental model mimicking human CD. The aim of this study was to characterize cytological and histological alterations in this model, and compare the results with those observed in human CD. Methods: Pregnant rats were given intraperitoneal injections of BCNU on E15. Sections of cerebral cortex from adult BCNU-treated rats were cytoarchitecturally and immunohistochemically analyzed using anti-SMI311, anticalbindin (CB), and antiparvalbumin (PV) antibodies. The density of the PVimmunoreactive (PV-ir) interneurons was quantitatively assessed by means of a two-dimensional cell-counting technique, and the spatial distribution of PV-ir neurons was evaluated by using the Voronoi tessellation. Results: The morphological features included reduced cortical size, laminar disorganization, and heterotopic clusters of neurons. We also identified large, disoriented SMI311-positive pyramidal neurons, and dysmorphic neurons intensely immunostained for neurofilaments, similar to those observed in human dysplastic cortex. An altered distribution of PV-immunoreactive cortical interneurons was also present. Conclusions: Although some of the cytoarchitectural abnormalities found in BCNU-exposed cortex are similar to those found in other CD models, we identified new alterations that recall the neuropathological description of type IIA (Taylor's type) CD. BCNU-treated rat could therefore be a useful additional model for investigating the pathogenic mechanisms involved in this CD.

Altered Migratory Behavior of Interneurons in a Model of Cortical Dysplasia: The Influence of Elevated GABAA Activity

“…Events that adversely impact the migratory process can lead to cortical dysplasia, a developmental abnormality characterized by aberrant cell clustering, altered gyral patterns, and changes in electrophysiological profile (Taylor et al 1971;Choi and Mathias 1987;Tassi et al 2002;Calcagnotto and Baraban 2003;Moroni et al 2008). The aberrations underlie a vast number of neurological/neuropsychiatric disorders including drug-resistant epilepsy, depression, and schizophrenia (Palmini et al 1991;Gleeson and Walsh 2000;Zhu and Roper 2000;Ross and Walsh 2001;Calcagnotto et al 2002).…”

Genesis of Heterotopia in BCNU Model of Cortical Dysplasia, Detected by Means of in utero Electroporation

“…1,3-Bis-chloroethyl-nitrosourea (BCNU)-treated rats represent a model of CD due to the presence of histological alterations similar to those observed in human CD. BCNU is an alkylating agent that, administered at embryonic day 15 (E15) at the peak of neurogenesis, causes the loss of many cells destined to cortical layers; this results in cortical thinning and also in histological alterations imputable to migration defects, such as laminar disorganization and cortical and periventricular heterotopia [8,9]. The cytological and histological alterations of this model have been widely investigated in both adult and developing animals by means of immunohistochemical markers recognizing interneurons or pyramidal neurons, by analyzing the expression pattern of an appropriate panel of cortical layer-specific genes and by using magnetic resonance imaging [9,10,11].…”

“…The cytological and histological alterations of this model have been widely investigated in both adult and developing animals by means of immunohistochemical markers recognizing interneurons or pyramidal neurons, by analyzing the expression pattern of an appropriate panel of cortical layer-specific genes and by using magnetic resonance imaging [9,10,11]. Changes in neocortical organization of BCNU-treated rats have been revealed since the embryonic stages, when the disorganization of the ventricular wall, the disruption of the radial and tangential fibers, and the defective organization of the CP and subplate can be observed [9,10,11]. …”

Targeted disruption of layer 4 during development increases GABAAreceptor neurotransmission in the neocortex

“…Events with adverse impact on neuronal migration lead to cortical dysplasia (CD), a developmental abnormality characterized by aberrant distribution and clustering of neocortical cells, resulting in a plethora of neuropathological disorders, such as epilepsy, schizophrenia, and mental retardation (Calcagnotto and Baraban 2003;Calcagnotto et al 2002;Choi and Mathias 1987;Colombo et al 2003;Gleeson and Walsh 2000;Guerrini et al 2003;Moroni et al 2005Moroni et al , 2008Palmini et al 1991;Ross and Walsh 2001;Tassi et al 2002;Taylor et al 1971;Zhu and Roper 2000). A common pathological finding in clinical cases and animal models of CD is an abnormal distribution and grouping of neurons within the neocortex, which alters the microcircuitry and cortical architecture (Benardete and Kriegstein 2002;Colacitti et al 1999;Ferrer 1993;Jacobs et al 1999;Moroni et al 2008;Roper 1998). In addition, abnormal GABA signaling frequently associates with CD, leading to consequent alteration in the balance of excitation and inhibition and disruption of normal cortical function (Benardete and Kriegstein 2002;Brill and Huguenard 2010;Moroni et al 2008;Roper et al 1999;Xiang et al 2006;Roper 2010, 2011;Zhu andRoper 2000, Zhu et al 2009).…”

“…A common pathological finding in clinical cases and animal models of CD is an abnormal distribution and grouping of neurons within the neocortex, which alters the microcircuitry and cortical architecture (Benardete and Kriegstein 2002;Colacitti et al 1999;Ferrer 1993;Jacobs et al 1999;Moroni et al 2008;Roper 1998). In addition, abnormal GABA signaling frequently associates with CD, leading to consequent alteration in the balance of excitation and inhibition and disruption of normal cortical function (Benardete and Kriegstein 2002;Brill and Huguenard 2010;Moroni et al 2008;Roper et al 1999;Xiang et al 2006;Roper 2010, 2011;Zhu andRoper 2000, Zhu et al 2009). …”