Kir4.1 is the principal K(+) channel expressed in glial cells. It has been shown that it plays a fundamental role in K(+)-spatial buffering, an astrocyte-specific process where excess extracellular concentration of K(+) ions, generated by synaptic activity, is spatially redistributed to distant sites via astrocytic syncytia. Experimental and clinical evidence suggested that abnormality of Kir4.1 function in the brain is involved in different neurological diseases such as epilepsy, dysmyelination, and Huntington's disease. Although it has been shown that Kir4.1 is expressed predominantly in astrocytes in certain areas of the rat brain and its transcript is present in the rat forebrain as early as embryonic day E14, no information is available concerning the temporal sequence of Kir4.1 protein appearance during embryonic and post-natal development. Aim of this work was to study the expression pattern of Kir4.1 channel in rat somatosensory cortex and hippocampus during development and to examine its cellular localization with the glial and oligodendroglial markers S100-β, GFAP, and Olig-2. Kir4.1 protein was detected since E20 and a gradual increase of Kir4.1 expression occurred between early postnatal period and adulthood. We showed a gradual shift in Kir4.1 subcellular localization from the soma of astrocytes to distal glial processes. Double immunofluorescence experiments confirmed the cellular localization of Kir4.1 in glial cells. Our data provide the first overview of Kir4.1 developmental expression both in the cortex and hippocampus and support the glial role of Kir4.1 in K(+) spatial buffering.

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Cortical dysplasias (CDs) include a spectrum of cerebral lesions resulting from cortical development abnormalities during embryogenesis that lead to cognitive disabilities and epilepsy. The experimental model of CD obtained by means of in utero administration of BCNU (1-3-bis-chloroethyl-nitrosurea) to pregnant rats on embryonic day 15 mimics the histopathological abnormalities observed in many patients. The aim of this study was to investigate the behavioural, electrophysiological and anatomical profile of BCNU-treated rats in order to determine whether cortical and hippocampal lesions can directly lead to cognitive dysfunction. The BCNU-treated rats showed impaired short-term working memory but intact long-term aversive memory, whereas their spontaneous motor activity and anxiety-like response were normal. The histopathological and immunohistochemical analyses, made after behavioural tests, revealed the disrupted integrity of neuronal populations and connecting fibres in hippocampus and prefrontal and entorhinal cortices, which are involved in memory processes. An electrophysiological evaluation of the CA1 region of in vitro hippocampal slices indicated a decrease in the efficiency of excitatory synaptic transmission and impaired paired pulse facilitation, but enhanced long-term potentiation (LTP) associated with hyperexcitability in BCNU-treated rats compared with controls. The enhanced LTP, associated with hyperexcitability, may indicate a pathological distortion of long-term plasticity. These findings suggest that prenatal developmental insults at the time of peak cortical neurogenesis can induce anatomical abnormalities associated with severe impairment of spatial working memory in adult BCNU-treated rats and may help to clarify the pathophysiological mechanisms of cognitive dysfunction that is often associated with epilepsy in patients with CD.

Superparamagnetic Au/Fe nanoparticles penetrate the brain parenchyma in an isolated guinea pig brain with an intact blood brain barrier.

SUMMARYObjective: Cortical dysplasias (CDs) represent a wide range of cortical abnormalities that closely correlate with intractable epilepsy. Rats prenatally exposed to 1-3-bischloroethyl-nitrosurea (BCNU) represent an injury-based model that reproduces many histopathologic features of human CD. Previous studies reported in vivo hyperexcitability in this model, but in vivo epileptogenicity has not been confirmed. Methods: To determine whether cortical and hippocampal lesions lead to epileptiform discharges and/or seizures in the BCNU model, rats at three different ages (3, 5, and 9 months old) were implanted for long-term video electroencephalographic recording. At the end of the recording session, brain tissue was processed for histologic and immunohistochemical investigation including cAMP response element binding protein (CREB) phosphorylation, as a biomarker of epileptogenicity. Results: BCNU-treated rats showed spontaneous epileptiform activity (67%) in the absence of a second seizure-provoking hit. Such activity originated mainly from one hippocampus and propagated to the ipsilateral neocortex. No epileptiform activity was found in age-matched control rats. The histopathologic investigation revealed that all BCNU rats with epileptiform activity showed neocortical and hippocampal abnormalities; the presence and the severity of these lesions did not correlate consistently with the propensity to generate epileptiform discharges. Epileptiform activity was found only in cortical areas of BCNU-treated rats in which a correlation between brain abnormalities and increased pCREB expression was observed. Significance: This study demonstrates the in vivo occurrence of spontaneous epileptiform discharges in the BCNU model and shows that increased pCREB expression can be utilized as a reliable biomarker of epileptogenicity.